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alpha-casein + H2O
?
-
best substrate
-
-
?
apocytochrome P450scc + H2O
?
-
bovine protein substrate from adrenal cortex mitochondrial inner membrane, imported in vitro into isolated yeast mitochondrial membrane, due to an N-terminal fusion to a heterologous transmembrane region
-
?
beta-casein + H2O
?
-
-
-
-
?
carbonylated membrane proteins + H2O
?
-
-
-
-
?
cytochrome c peroxidase + H2O
?
cytochrome c peroxidase 1 + H2O
?
HMG1-phosphorylated mitochondrial transcription factor A + H2O
?
-
-
-
-
?
hybrid protein + H2O
2 peptide fragments f2 and f3
-
hybrid protein of subunit 2 of cytochrome oxidase residues 1-74, mouse dihydrofolate reductase, and mitochondrial presequence, residues 1-66, of subunit 9 of the ATPase of Neurospora crassa, in vitro import into the mitochondrion
product characterization
?
kappa-casein + H2O
?
-
-
-
-
?
mitochondrial integral inner membrane protein Mgm1 + H2O
?
mitochondrial integral inner membrane protein Yme2p + H2O
?
Oma1 + H2O
?
substrate is a zinc metallopeptidase of the inner mitochondrial membrane
-
-
?
protein Atp7 + H2O
?
-
subunit of F1Fo-ATP synthase, peripheral membrane protein
-
-
?
protein Cob + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein Cox1 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein Cox3 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein F0 subunit 6 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein F0 subunit 8 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein F0 subunit 9 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein OAP1 + H2O
?
-
homo-oligomeric m-AAA protease complexes composed of murine Afg3l1, Afg3l2, or human AFG3L2 subunits cleave OPA1 with higher efficiency than paraplegin-containing m-AAA proteases
-
-
?
residues 1-74 of subunit 2 of cytochrome oxidase + H2O
?
-
two-step procedure, in vitro import into the mitochondrion
-
?
rhodamine 110, bis-(Cbz-L-alanyl-L-alanine amide) + H2O
?
-
-
-
-
?
unassembled cytochrome oxidase 2 + H2O
?
-
-
-
?
additional information
?
-
Ccp1 precursor + H2O
?
-
i.e. cytochrome c peroxidase, natural substrate
-
-
?
Ccp1 precursor + H2O
?
-
i.e. cytochrome c peroxidase, natural substrate
-
-
?
cytochrome c peroxidase + H2O
?
-
-
-
-
?
cytochrome c peroxidase + H2O
?
-
the m-AAA protease is enriched in the inner boundary membrane of mitochondria. The membrane-anchored precursor form of cytochrome c peroxidase (pCcp1) is preferentially localized in this subdomain of the inner membrane. On processing by the m-AAA protease and rhomboid protease Pcp1, the mature Ccp1 is released and moves into the cristae space
-
-
?
cytochrome c peroxidase 1 + H2O
?
-
mediates the ATP-dependent membrane dislocation of cytochrome c peroxidase 1 independent of its proteolytic activity, it thereby ensures the correct positioning of cytochrome c peroxidase 1 within the membrane bilayer allowing intramembrane cleavage by rhomboid
-
-
?
cytochrome c peroxidase 1 + H2O
?
-
cleaved at Ala29 in the middle of the hydrophobic segment by the inner membrane m-AAA protease complex
-
-
?
cytochrome c peroxidase 1 + H2O
?
-
cleaved at Ala29 in the middle of the hydrophobic segment by the inner membrane m-AAA protease complex
-
-
?
mitochondrial integral inner membrane protein Mgm1 + H2O
?
-
-
-
-
?
mitochondrial integral inner membrane protein Mgm1 + H2O
?
-
-
-
-
?
mitochondrial integral inner membrane protein Yme2p + H2O
?
-
-
-
-
?
mitochondrial integral inner membrane protein Yme2p + H2O
?
-
wild-type and chimeric mutant containing the dihydrofolate reductase loosely folded mutant, not the one containing the wild-type dihydrofolate reductase, overview, unfolding of the substrate at one side of the membrane might be sufficient for proteolysis, in vitro synthesized protein substrate, imported into the mitochondria, spans the membrane once and exposes large domains at both membrane surfaces
-
?
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
MrpL32 + H2O
?
-
yeast mitochondrial ribosomal protein
-
-
?
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
MrpL32 + H2O
?
-
mitochondrial ribosomal protein, enzyme mediates processing of newly imported MrpL32. Maturation in vivo depends on enzyme
-
-
?
MrpL32 + H2O
?
-
mitochondrial ribosomal protein, enzyme mediates processing of newly imported MrpL32
-
-
?
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
MrpL32 + H2O
?
-
m-AAA protease initiates proteolysis from the N-terminus of MrpL32. Oxidative stress impairs folding of MrpL32, resulting in its degradation by the m-AAA protease
-
-
?
MrpL32 + H2O
?
-
MrpL32 receives processing by the m-AAA protease after import into the matrix
-
-
?
protein + H2O
peptides
-
unfoldase activity might be a common property of ATP-dependent proteases
-
?
protein + H2O
peptides
-
enzyme is essential for cell viability, the enzyme affects the splicing of transcripts of mitochondrial genes encoding essential respiratory complexes and the ATP synthase, degradation of membrane proteins, essentially required as a membrane-integrated quality control, inactivation of AAA proteases cause severe defects in various organisms, including neurodegeneration in humans
-
?
protein + H2O
peptides
-
-
-
?
protein + H2O
peptides
-
-
-
?
protein + H2O
peptides
-
-
?
protein + H2O
peptides
-
activity depends on oligomerisation
-
?
protein + H2O
peptides
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
product peptides in the matrix space are actively transported across the inner membrane by an ABC transporter Mdl1
?
protein + H2O
peptides
-
degradation of proteins exposing loops or domain at either sides of the mitochondrial inner membrane
-
?
protein + H2O
peptides
-
enzyme probably forms a pore-like structure facilitating the transport of hydrophilic parts of the substrate protein during its extraction, limited substrate recognition
product peptides in the matrix space are actively transported across the inner membrane by an ABC transporter Mdl1
?
protein + H2O
peptides
-
degradation of mislocalized proteins in the mitochodria
-
?
protein + H2O
peptides
-
enzyme is essential for cell viability, the enzyme affects the splicing of transcripts of mitochondrial genes encoding essential respiratory complexes and the ATP synthase, degradation of membrane proteins, essentially required as a membrane-integrated quality control, inactivation of AAA proteases cause severe defects in various organisms, including neurodegeneration in humans
-
?
protein + H2O
peptides
-
important role in the removal of non-assembled polypeptides from the inner membrane, inactivation of the enzyme is lethal, loss of activity causes respiration-deficiency, affects the splicing of transcripts of mitochondrial genes encoding essential respiratory chain subunits and controls the post-translational asembly of respiratory complexes and the ATP synthase, required as a membrane-integrated quality control to facilitate protein folding and to ensure the selective removal of non-native polypeptides
-
?
protein + H2O
peptides
-
quality control system to selectively remove non-assembled polypeptides and to prevent their possible deleterious accumulation in the membrane, enzyme is crucial for viability
-
?
additional information
?
-
-
shedding model for availability of water molecules: enzyme shed solvent exposed loops or domains from membrane-embedded polypeptides, pulling model: binding of unfolded substrate protein segments together with ATP-dependent conformational changes in the enzyme can provide a pulling force on membrane proteins, with the enzyme being embedded in the bilayer
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration
-
-
?
additional information
?
-
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
additional information
?
-
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
additional information
?
-
-
DNA-bound mitochondrial transcription factor A is resistant to proteolysis
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
-
construction of several deletion mutants of Yme2p and investigation of their behaviour as substrates, overview, the folded intermembrane space domain of Yme2p prevents proteolysis but not protease binding at the opposite membrane side
-
?
additional information
?
-
-
Yta12p enzyme requires YTA10-12 complex formation for activity
-
?
additional information
?
-
-
m-AAA protease ensures maturation of cytochrome c peroxidase 1 (Ccp1). The precursor of Ccp1 is dislocated from the inner mitochondrial membrane to allow cleavage by the rhomboid protease Pcp1. Dislocation depends on the ATPase but not the proteolytic activity of the m-AAA protease
-
-
?
additional information
?
-
-
Mgm1 is not a substrate of the enzyme
-
-
?
additional information
?
-
-
Mgm1 is not a substrate of the enzyme
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
carbonylated membrane proteins + H2O
?
-
-
-
-
?
cytochrome c peroxidase + H2O
?
-
the m-AAA protease is enriched in the inner boundary membrane of mitochondria. The membrane-anchored precursor form of cytochrome c peroxidase (pCcp1) is preferentially localized in this subdomain of the inner membrane. On processing by the m-AAA protease and rhomboid protease Pcp1, the mature Ccp1 is released and moves into the cristae space
-
-
?
cytochrome c peroxidase 1 + H2O
?
HMG1-phosphorylated mitochondrial transcription factor A + H2O
?
-
-
-
-
?
protein Atp7 + H2O
?
-
subunit of F1Fo-ATP synthase, peripheral membrane protein
-
-
?
protein Cob + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein Cox1 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein Cox3 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein F0 subunit 6 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein F0 subunit 8 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
protein F0 subunit 9 + H2O
?
-
degradation of membrane proteins, essentially required as a membrane-integrated quality control
-
?
unassembled cytochrome oxidase 2 + H2O
?
-
-
-
?
additional information
?
-
Ccp1 precursor + H2O
?
-
i.e. cytochrome c peroxidase, natural substrate
-
-
?
Ccp1 precursor + H2O
?
-
i.e. cytochrome c peroxidase, natural substrate
-
-
?
cytochrome c peroxidase 1 + H2O
?
-
cleaved at Ala29 in the middle of the hydrophobic segment by the inner membrane m-AAA protease complex
-
-
?
cytochrome c peroxidase 1 + H2O
?
-
cleaved at Ala29 in the middle of the hydrophobic segment by the inner membrane m-AAA protease complex
-
-
?
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
MrpL32 + H2O
?
-
mitochondrial ribosomal protein, enzyme mediates processing of newly imported MrpL32. Maturation in vivo depends on enzyme
-
-
?
MrpL32 + H2O
?
-
in vivo substrate, m-AAA does not affect the stability of the protein but cleaves the N-terminal mitochondrial targeting sequence upon protein import into the mitochondrion
-
-
?
MrpL32 + H2O
?
-
m-AAA protease initiates proteolysis from the N-terminus of MrpL32. Oxidative stress impairs folding of MrpL32, resulting in its degradation by the m-AAA protease
-
-
?
MrpL32 + H2O
?
-
MrpL32 receives processing by the m-AAA protease after import into the matrix
-
-
?
protein + H2O
peptides
-
enzyme is essential for cell viability, the enzyme affects the splicing of transcripts of mitochondrial genes encoding essential respiratory complexes and the ATP synthase, degradation of membrane proteins, essentially required as a membrane-integrated quality control, inactivation of AAA proteases cause severe defects in various organisms, including neurodegeneration in humans
-
?
protein + H2O
peptides
-
-
-
?
protein + H2O
peptides
-
-
?
protein + H2O
peptides
-
degradation of proteins exposing loops or domain at either sides of the mitochondrial inner membrane
-
?
protein + H2O
peptides
-
degradation of mislocalized proteins in the mitochodria
-
?
protein + H2O
peptides
-
enzyme is essential for cell viability, the enzyme affects the splicing of transcripts of mitochondrial genes encoding essential respiratory complexes and the ATP synthase, degradation of membrane proteins, essentially required as a membrane-integrated quality control, inactivation of AAA proteases cause severe defects in various organisms, including neurodegeneration in humans
-
?
protein + H2O
peptides
-
important role in the removal of non-assembled polypeptides from the inner membrane, inactivation of the enzyme is lethal, loss of activity causes respiration-deficiency, affects the splicing of transcripts of mitochondrial genes encoding essential respiratory chain subunits and controls the post-translational asembly of respiratory complexes and the ATP synthase, required as a membrane-integrated quality control to facilitate protein folding and to ensure the selective removal of non-native polypeptides
-
?
protein + H2O
peptides
-
quality control system to selectively remove non-assembled polypeptides and to prevent their possible deleterious accumulation in the membrane, enzyme is crucial for viability
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration
-
-
?
additional information
?
-
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
additional information
?
-
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons
-
-
?
additional information
?
-
-
DNA-bound mitochondrial transcription factor A is resistant to proteolysis
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
strong genetic interaction between Afg3l2 and Spg7 in adult neurons, indicating that both m-AAA protease isoenzymes are required to prevent degenerative changes. The m-AAA protease protects against cerebellar degeneration. Spg72/2 mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. m-AAA protease affects mt-DNA content and stability of the respiratory complexes
-
-
?
additional information
?
-
-
m-AAA protease ensures maturation of cytochrome c peroxidase 1 (Ccp1). The precursor of Ccp1 is dislocated from the inner mitochondrial membrane to allow cleavage by the rhomboid protease Pcp1. Dislocation depends on the ATPase but not the proteolytic activity of the m-AAA protease
-
-
?
additional information
?
-
-
Mgm1 is not a substrate of the enzyme
-
-
?
additional information
?
-
-
Mgm1 is not a substrate of the enzyme
-
-
?
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malfunction
involved in hereditary spastic paraplegias
malfunction
-
enzyme knockdown in HeLa cells results in enlarged mitochondrial DNA nucleoids
malfunction
-
enzyme knockdown stabilizes mitochondrial transcription factor A in mitochondrial DNA-deficient cells and upregulates mitochondrial DNA DNA
malfunction
-
mutations in subunit AFG3L2 are associated with spinocerebellar ataxia SCA28. Depletion of subunit AFG3L2 leads to a specific defect of anterograde transport of mitochondria in cortical neurons. Deletion of subunit AFG3L2 in adult cortical neurons causes tau hyperphosphorylation and activation of protein kinase A and ERK1/2 kinases
metabolism
-
the m-AAA protease dislocates transmembrane segments from the mitochondrial inner membrane. The presence of the m-AAA protease increases the hydrophobicity required for a transmembrane segment to remain in the membrane. The m-AAA protease is a central component of the mitochondrial protein quality control system, being able to extract and degrade misfolded polypeptides from the inner membrane
metabolism
-
the m-AAA protease dislocates transmembrane segments from the mitochondrial inner membrane. The presence of the m-AAA protease increases the hydrophobicity required for a transmembrane segment to remain in the membrane. The m-AAA protease is a central component of the mitochondrial protein quality control system, being able to extract and degrade misfolded polypeptides from the inner membrane
-
physiological function
-
mutations in the mitochondrial m-AAA protease genes cause two different neurodegenerative diseases in humans
physiological function
mutations in the SPG7 gene (paraplegin) cause an autosomal recessive form of hereditary spastic paraplegias
physiological function
-
regulates OPA1 cleavage in mitochondrial inner membrane
physiological function
regulates OPA1 cleavage in mitochondrial inner membrane
physiological function
-
MrpL32 ribosomal subunit processing is the central process controlled by the m-AAA protease in yeast
physiological function
-
subunit AFG3L2 is required cell-autonomously for survival of adult neurons
physiological function
-
the enzyme is a crucial component of the defense against accumulation of carbonylated proteins
physiological function
-
the enzyme maintains mitochondrial DNA nucleoid distribution through mitochondrial transcription factor A function as a chaperone rather than as a protease and is involvement in mitochondrial DNA segregation
physiological function
astrocyte-specific deletion of Afg3l2 in the mouse leads to late-onset motor impairment and to degeneration of Bergmann glia, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both subunits Afg31l and Afg3l2. Mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted Bergmann glia show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Astrocyte-specific deficiency of Afg3l1 and Afg3l2 triggers secondary morphological degeneration and electrophysiological changes in Purkinje cells
physiological function
both m-AAA and i-AAA complexes coordinately regulate OMA1 processing and turnover, and consequently control which OPA1 isoforms are present
physiological function
deletion of subunit AFG3L2 in mature mouse oligodendrocytes provokes early-on mitochondrial fragmentation and swelling. Total ablation of the m-AAA protease, by deleting both Afg3l2 and its paralogue Afg3l1, triggers progressive motor dysfunction and demyelination, owing to rapid oligodendrocyte cell death. The mice show premature hair greying, caused by progressive loss of melanoblasts
physiological function
in a mechanistic model, the ATP-bound subunits bind substrate, whereas the ADP-bound subunit releases the substrate at the lowest position of the spiral staircase, and the nucleotide-free subunit transitions to the highest position of the spiral staircase, where it reattaches to the substrate upon ATP-binding. The unfolded substrate is translocated in this fashion toward the negatively charged proteolytic chamber, where it is positioned for cleavage at the zinc-coordinated active site of the immutable planar protease domains
physiological function
loss of subunits AFG3L2 and YME1L, both alone and in combination, results in diminished cell proliferation, fragmentation of mitochondrial reticulum, altered cristae morphogenesis, and defective respiratory chain biogenesis. The double AFG3L2/YME1L knockdown cells show marked upregulation of dynamin-like protein OPA1 protein forms, with the most prominent increase in short OPA1 (optic atrophy 1). Loss of either protease leads to marked elevation in OMA1 zinc metallopeptidase and severe reduction in the SPG7 (paraplegin) subunit of the m-AAA complex. Loss of the YME1L subunit leads to an increased Drp1 level in mitochondrial fractions. Loss of YME1L impairs biogenesis and function of complex I, knockdown of AFG3L2 mainly affects the assembly and function of complex IV
physiological function
loss of the SPG7 gene increased resistance to Ca2+-induced mitochondrial permeability transition pore opening. This occurs independently of cyclophilin D (cyclosporine A insensitive) but rather it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca2+ uniporter complexes. SPG7 directs the m-AAA complex to favor association with the mitochondrial Ca2+ uniporter, and mitochondrial Ca2+ uniporter processing regulates higher order mitochondrial Ca2+ uniporter-complex formation
physiological function
-
protease AFG3L2 is a caveolin-1-interacting protein in vitro. Oxidative stress promotes the translocation of both caveolin-1 and AFG3L2 to mitochondria, enhances the interaction of caveolin-1 with AFG3L2 in mitochondria and stimulates mitochondrial protease activity in wild-type fibroblasts. Localization of AFG3L2 to mitochondria after oxidative stress is inhibited in fibroblasts lacking caveolin-1, which results in impaired mitochondrial protein quality control, an oxidative phosphorylation to aerobic glycolysis switch and reduced ATP production. Expression of a mutant form of AFG3L2 with reduced affinity for caveolin-1, fails to localize to mitochondria and promotes degradation of complex IV after oxidative stress
physiological function
-
replacement of the subunit Yta10 TM2 domain abolishes membrane dislocation for only a subset of substrates, whereas replacement of the subunit Yta12 TM2 domain impairs membrane dislocation for all substrates tested. m-AAA protease-mediated membrane dislocation is impaired in the presence of a large downstream hydrophilic moiety in a membrane substrate
physiological function
SPG7 mutants exhibit shortened lifespan, progressive locomotor defects, sensitivity to chemical and environmental stress, and muscular and neuronal degeneration. The neurodegenerative phenotype of SPG7 mutants initiates at the synaptic terminal. A variety of mitochondrial defects are observed in the mutants, including altered axonal transport of mitochondria, accumulation of electron-dense material in the matrix of flight muscle mitochondria, reduced activities of respiratory chain complexes I and II, and severely swollen and dysmorphic mitochondria in the synaptic terminals of photoreceptors
physiological function
-
in a mechanistic model, the ATP-bound subunits bind substrate, whereas the ADP-bound subunit releases the substrate at the lowest position of the spiral staircase, and the nucleotide-free subunit transitions to the highest position of the spiral staircase, where it reattaches to the substrate upon ATP-binding. The unfolded substrate is translocated in this fashion toward the negatively charged proteolytic chamber, where it is positioned for cleavage at the zinc-coordinated active site of the immutable planar protease domains
-
physiological function
-
replacement of the subunit Yta10 TM2 domain abolishes membrane dislocation for only a subset of substrates, whereas replacement of the subunit Yta12 TM2 domain impairs membrane dislocation for all substrates tested. m-AAA protease-mediated membrane dislocation is impaired in the presence of a large downstream hydrophilic moiety in a membrane substrate
-
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A510V
subunit paraplegin, function impaired, naturally occuring pathogenic mutation
E359A
-
the mutant lacks ATPase activity but retains casein lytic protease activity
E408Q
subunit AFG3L2, within Walker B motif, cells expressing AFG3L2 (E408Q) show a prominent reduction of their growth rate
F381A
substitution abolishes substrate degradation, while only mildly impacting ATP hydrolysis
G349S
subunit paraplegin, function impaired, naturally occuring pathogenic mutation
K354A
subunit AFG3L2, homo-oligomeric complex inactive
M380K
mutation completely abolishes AFG3L2 activity
M683A
mutation moderately reduces substrate degradation while minimally affecting ATP hydrolysis
N432T
disease-relevant mutation, localizes to the vicinity of the nucleotide-binding pocket at the ATPase intersubunit interface
R468C
disease-relevant mutation, localizes to the vicinity of the nucleotide-binding pocket at the ATPase intersubunit interface
R688Q
subunit paraplegin, polymorphism, naturally occuring mutation
T503A
subunit paraplegin, polymorphism, naturally occuring mutation
W583C
subunit paraplegin, function impaired, naturally occuring pathogenic mutation
E567Q
-
catalytically inactive
E574Q
-
catalytically inactive
D634A
-
catalytically inactive
D689A
-
catalytically inactive
E388Q/E448Q
-
an ATP hydrolysis-deficient m-AAA protease variant. The mutant effectively traps ATP and keeps m-AAA protease subunits in one nucleotide conformation
E575Q
subunit AFG3L2, homo-oligomeric complex inactive
E575Q
subunit AFG3L2, within proteolytic site, no effect on growth rate
E559Q
-
inactive mutant
E559Q
-
of subunit Yta10, enzyme is still capable of substrate binding but lacks proteolytic activity
E559Q
-
exerts only about 10% of wild type activity
E614Q
-
inactive mutant
E614Q
-
site-directed mutagenesis, exchange of active site residue, stongly reduced activity
E614Q
-
of subunit Yta12, enzyme is still capable of substrate binding but lacks proteolytic activity
E614Q
-
exerts only about 10% of wild type activity
additional information
-
mutant enzyme variants are sufficient to suppress growth defects of the respective null-mutant cells
additional information
deleting the ordered, substrate-interacting ATPase N terminus (residues 272-295) significantly impaires substrate degradation. Truncation of the C-terminus at residue 750, decreases recovery ofAFG3L2 hexamers
additional information
-
deleting the ordered, substrate-interacting ATPase N terminus (residues 272-295) significantly impaires substrate degradation. Truncation of the C-terminus at residue 750, decreases recovery ofAFG3L2 hexamers
additional information
-
deletion of subunit paraplegin, maturation of yeast MrpL32 protein is impaired. Functional conservation of yeast Yta10/Yta12 and murine paraplegin/Afg3L2
additional information
-
truncated variants of paraplegin
additional information
-
in a mutant form of AFG3L2, in which the aromatic residues within the caveolin-1-binding domain are substituted with alanines, the interaction with caveolin-1 is dramatically compromised
additional information
-
construction of chimeric protein substrates: 1. the matrix domain of Yme2p is replaced by mouse dihydrofolate reductase, 2. a chimeric protein consisting of a loosely folded mutant variant of dihydrofolate reductase and the C-terminal end of Yme2p
additional information
-
inactivation of the enzyme impairs respiratory competence
additional information
-
deletion of either subunit Yta10 or Yta12, partial stabilization of substrate Atp7. Deletion of transmembrane segments of either subunit Yta10 or Yta12, enzyme retains proteolytic activity, but proteolsis of integral membrane proteins is impaired. Transmembrane segments of enzyme have a direct role in the dislocation of membrane-embedded subsrates
additional information
-
deletion of either subunit Yta10 or Yta12, synthesis of mitochondrially encoded proteins is strongly impaired
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Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M.C.; Estreicher, A.; Gasteiger, E.; Martin M.J.; Michoud, K.; O'Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M.
The SWISS-PROT protein knowledgebase and its supplement TrEMBL
Nucleic Acids Res.
31
365-370
2003
Saccharomyces cerevisiae (P40341)
brenda
Langer, T.; Kaser, M.; Klanner, C.; Leonhard, K.
AAA proteases of mitochondria: quality control of membrane proteins and regulatory functions during mitochondrial biogenesis
Biochem. Soc. Trans.
29
431-436
2001
Saccharomyces cerevisiae, eukaryota
brenda
Arnold, I.; Langer, T.
Membrane protein degradation by AAA proteases in mitochondria
Biochim. Biophys. Acta
1592
89-96
2002
Saccharomyces cerevisiae
brenda
Leonhard, K.; Herrmann, J.M.; Stuart, R.A.; Mannhaupt, G.; Neupert, W.; Langer, T.
AAA proteases with catalytic sites on opposite membrane surfaces comprise a proteolytic system for the ATP-dependent degradation of inner membrane proteins in mitochondria
EMBO J.
15
4218-4229
1996
Saccharomyces cerevisiae
brenda
Savel'ev, A.S.; Novikova, L.A.; Kovaleva, I.E.; Luzikov, V.N.; Neupert, W.; Langer, T.
ATP-dependent proteolysis in mitochondria. m-AAA protease and PIM1 protease exert overlapping substrate specificities and cooperate with the mtHsp70 system
J. Biol. Chem.
273
20596-20602
1998
Saccharomyces cerevisiae
brenda
Leonhard, K.; Guiard, B.; Pellecchia, G.; Tzagoloff, A.; Neupert, W.; Langer, T.
Membrane protein degradation by AAA proteases in mitochondria: extraction of substrates from either membrane surface
Mol. Cell
5
629-638
2000
Saccharomyces cerevisiae
brenda
Nolden, M.; Ehses, S.; Koppen, M.; Bernacchia, A.; Rugarli, E.I.; Langer, T.
The m-AAA protease defective in hereditary spastic paraplegia controls ribosome assembly in mitochondria
Cell
123
277-289
2005
Saccharomyces cerevisiae, Mus musculus
brenda
Korbel, D.; Wurth, S.; Kaeser, M.; Langer, T.
Membrane protein turnover by the m-AAA protease in mitochondria depends on the transmembrane domains of its subunits
EMBO Rep.
5
698-703
2004
Saccharomyces cerevisiae
brenda
Tatsuta, T.; Augustin, S.; Nolden, M.; Friedrichs, B.; Langer, T.
m-AAA protease-driven membrane dislocation allows intramembrane cleavage by rhomboid in mitochondria
EMBO J.
26
325-335
2007
Saccharomyces cerevisiae
brenda
Smith, D.G.; Gawryluk, R.M.; Spencer, D.F.; Pearlman, R.E.; Siu, K.W.; Gray, M.W.
Exploring the mitochondrial proteome of the ciliate protozoon Tetrahymena thermophila: direct analysis by tandem mass spectrometry
J. Mol. Biol.
374
837-863
2007
Tetrahymena thermophila
brenda
Duvezin-Caubet, S.; Koppen, M.; Wagener, J.; Zick, M.; Israel, L.; Bernacchia, A.; Jagasia, R.; Rugarli, E.I.; Imhof, A.; Neupert, W.; Langer, T.; Reichert, A.S.
OPA1 processing reconstituted in yeast depends on the subunit composition of the m-AAA protease in mitochondria
Mol. Biol. Cell
18
3582-3590
2007
Mus musculus
brenda
Koppen, M.; Metodiev, M.D.; Casari, G.; Rugarli, E.I.; Langer, T.
Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia
Mol. Cell. Biol.
27
758-767
2007
Mus musculus
brenda
Rugarli, E.I.; Langer, T.
Translating m-AAA protease function in mitochondria to hereditary spastic paraplegia
Trends Mol. Med.
12
262-269
2006
Saccharomyces cerevisiae, Homo sapiens, Mus musculus
brenda
Martinelli, P.; La Mattina, V.; Bernacchia, A.; Magnoni, R.; Cerri, F.; Cox, G.; Quattrini, A.; Casari, G.; Rugarli, E.I.
Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration
Hum. Mol. Genet.
18
2001-2013
2009
Mus musculus (Q3ULF4), Mus musculus (Q8JZQ2), Homo sapiens (Q9UQ90), Homo sapiens (Q9Y4W6), Homo sapiens
brenda
Suppanz, I.E.; Wurm, C.A.; Wenzel, D.; Jakobs, S.
The m-AAA protease processes cytochrome c peroxidase preferentially at the inner boundary membrane of mitochondria
Mol. Biol. Cell
20
572-580
2009
Saccharomyces cerevisiae
brenda
Sacco, T.; Boda, E.; Hoxha, E.; Pizzo, R.; Cagnoli, C.; Brusco, A.; Tempia, F.
Mouse brain expression patterns of Spg7, Afg3l1, and Afg3l2 transcripts, encoding for the mitochondrial m-AAA protease
BMC Neurosci.
11
55
2010
Mus musculus
brenda
Bonn, F.; Pantakani, K.; Shoukier, M.; Langer, T.; Mannan, A.U.
Functional evaluation of paraplegin mutations by a yeast complementation assay
Hum. Mutat.
31
617-621
2010
Homo sapiens (Q9UQ90), Homo sapiens
brenda
Ehses, S.; Raschke, I.; Mancuso, G.; Bernacchia, A.; Geimer, S.; Tondera, D.; Martinou, J.C.; Westermann, B.; Rugarli, E.I.; Langer, T.
Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1
J. Cell Biol.
187
1023-1036
2009
Mus musculus, Homo sapiens (Q9Y4W6), Homo sapiens
brenda
Koppen, M.; Bonn, F.; Ehses, S.; Langer, T.
Autocatalytic processing of m-AAA protease subunits in mitochondria
Mol. Biol. Cell
20
4216-4224
2009
Mus musculus
brenda
Karlberg, T.; van den Berg, S.; Hammarstroem, M.; Sagemark, J.; Johansson, I.; Holmberg-Schiavone, L.; Schueler, H.
Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7
PLoS ONE
4
e6975
2009
Homo sapiens (Q9UQ90), Homo sapiens
brenda
Gerdes, F.; Tatsuta, T.; Langer, T.
Mitochondrial AAA proteases - Towards a molecular understanding of membrane-bound proteolytic machines
Biochim. Biophys. Acta
1823
49-55
2012
Saccharomyces cerevisiae
brenda
Bonn, F.; Tatsuta, T.; Petrungaro, C.; Riemer, J.; Langer, T.
Presequence-dependent folding ensures MrpL32 processing by the m-AAA protease in mitochondria
EMBO J.
30
2545-2556
2011
Saccharomyces cerevisiae
brenda
Lee, S.; Augustin, S.; Tatsuta, T.; Gerdes, F.; Langer, T.; Tsai, F.T.
Electron cryomicroscopy structure of a membrane-anchored mitochondrial AAA protease
J. Biol. Chem.
286
4404-4411
2011
Saccharomyces cerevisiae
brenda
Smakowska, E.; Czarna, M.; Janska, H.
Mitochondrial ATP-dependent proteases in protection against accumulation of carbonylated proteins
Mitochondrion
19
245-251
2014
Homo sapiens
brenda
Kondadi, A.K.; Wang, S.; Montagner, S.; Kladt, N.; Korwitz, A.; Martinelli, P.; Herholz, D.; Baker, M.J.; Schauss, A.C.; Langer, T.; Rugarli, E.I.
Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation
EMBO J.
33
1011-1026
2014
Mus musculus
brenda
Kasashima, K.; Sumitani, M.; Endo, H.
Maintenance of mitochondrial genome distribution by mitochondrial AAA+ protein ClpX
Exp. Cell Res.
318
2335-2343
2012
Homo sapiens
brenda
Ramelot, T.A.; Yang, Y.; Sahu, I.D.; Lee, H.W.; Xiao, R.; Lorigan, G.A.; Montelione, G.T.; Kennedy, M.A.
NMR structure and MD simulations of the AAA protease intermembrane space domain indicates peripheral membrane localization within the hexaoligomer
FEBS Lett.
587
3522-3528
2013
Homo sapiens, Homo sapiens (Q9Y4W6)
brenda
Botelho, S.C.; Tatsuta, T.; von Heijne, G.; Kim, H.
Dislocation by the m-AAA protease increases the threshold hydrophobicity for retention of transmembrane helices in the inner membrane of yeast mitochondria
J. Biol. Chem.
288
4792-4798
2013
Saccharomyces cerevisiae, Saccharomyces cerevisiae W303-1A
brenda
Lowth, B.; Kirstein-Miles, J.; Saiyed, T.; Brtz-Oesterhelt, H.; Morimoto, R.; Truscott, K.; Dougan, D.
Substrate recognition and processing by a Walker B mutant of the human mitochondrial AAA+ protein CLPX
J. Struct. Biol.
179
193-201
2012
Homo sapiens
brenda
Lu, B.; Lee, J.; Nie, X.; Li, M.; Morozov, Y.I.; Venkatesh, S.; Bogenhagen, D.F.; Temiakov, D.; Suzuki, C.K.
Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease
Mol. Cell
49
121-132
2013
Homo sapiens
brenda
Volonte, D.; Liu, Z.; Shiva, S.; Galbiati, F.
Caveolin-1 controls mitochondrial function through regulation of m-AAA mitochondrial protease
Aging
8
2355-2369
2016
Mus musculus
brenda
Pareek, G.; Thomas, R.; Pallanck, L.
Loss of the Drosophila m-AAA mitochondrial protease paraplegin results in mitochondrial dysfunction, shortened lifespan, and neuronal and muscular degeneration article
Cell Death Dis.
9
304
2018
Drosophila melanogaster (Q9W4W8)
brenda
Murru, S.; Hess, S.; Barth, E.; Almajan, E.R.; Schatton, D.; Hermans, S.; Brodesser, S.; Langer, T.; Kloppenburg, P.; Rugarli, E.I.
Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration
Glia
67
1526-1541
2019
Mus musculus (Q920A7 and Q8JZQ2), Mus musculus
brenda
Cesnekova, J.; Rodinova, M.; Hansikova, H.; Zeman, J.; Stiburek, L.
Loss of mitochondrial AAA proteases AFG3L2 and YME1L impairs mitochondrial structure and respiratory chain biogenesis
Int. J. Mol. Sci.
19
e9288
2018
Homo sapiens (Q9Y4W6 and Q96TA2)
brenda
Lee, S.; Lee, H.; Yoo, S.; Kim, H.
Molecular insights into the m-AAA protease-mediated dislocation of transmembrane helices in the mitochondrial inner membrane
J. Biol. Chem.
292
20058-20066
2017
Saccharomyces cerevisiae, Saccharomyces cerevisiae W303-1A
brenda
Hurst, S.; Baggett, A.; Csordas, G.; Sheu, S.S.
SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2+ influx, and regulation of mitochondrial permeability transition pore opening
J. Biol. Chem.
294
10807-10818
2019
Homo sapiens (Q9UQ90 and Q9Y4W6)
brenda
Consolato, F.; Maltecca, F.; Tulli, S.; Sambri, I.; Casari, G.
m-AAA and i-AAA complexes coordinate to regulate OMA1, the stress-activated supervisor of mitochondrial dynamics
J. Cell Sci.
131
jcs213546
2018
Mus musculus (Q8JZQ2)
brenda
Puchades, C.; Ding, B.; Song, A.; Wiseman, R.; Lander, G.; Glynn, S.
Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease
Mol. Cell.
75
1073-1085
2019
Homo sapiens (Q9Y4W6), Homo sapiens
brenda
Wang, S.; Jacquemyn, J.; Murru, S.; Martinelli, P.; Barth, E.; Langer, T.; Niessen, C.; Rugarli, E.
The mitochondrial m-AAA protease prevents demyelination and hair greying
PLoS Genet.
12
e1006463
2016
Mus musculus (Q8JZQ2), Mus musculus
brenda
Puchades, C.; Rampello, A.; Shin, M.; Giuliano, C.; Wiseman, R.; Glynn, S.; Lander, G.
Atomic structure of the mitochondrial inner membrane AAA+ protease YME1 reveals the mecanism of substrate processing
Science
358
6363
2017
Saccharomyces cerevisiae (B3LL85), Saccharomyces cerevisiae RM11-1a (B3LL85)
brenda