Literature summary for 2.7.3.2 extracted from

Schlattner, U.; Klaus, A.; Ramirez Rios, S.; Guzun, R.; Kay, L.; Tokarska-Schlattner, M.
Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites (2016), Amino Acids, 48, 1751-1774.

Cloned(Commentary)

Cloned (Comment)	Organism
gene Ckb, brain cDNA library screening for enzyme interaction partners	Rattus norvegicus

Protein Variants

Protein Variants	Comment	Organism
additional information	construction of an N-terminally trucated isozyme BCK	Rattus norvegicus

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
cytoskeleton	recruitment of BCK to submembrane domains, formation of dynamic actin-based protrusions	Mus musculus	5856	-
cytosol	cytosolic brain-type creatine kinase	Mus musculus	5829	-
cytosol	cytosolic brain-type creatine kinase, mainly soluble brain BCK	Rattus norvegicus	5829	-
endoplasmic reticulum	-	Mus musculus	5783	-
endoplasmic reticulum	isozyme BCK localization at the endoplasmic reticulum calcium pump is regulated by phosphorylation via AMPK	Rattus norvegicus	5783	-
membrane	-	Mus musculus	16020	-
membrane	association of brain-type creatine kinase with membrane structures such as synaptic vesicles and mitochondria, involving hydrophobic and electrostatic interactions, respectively. Membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations. Recruitment of BCK to submembrane domains also supports formation of dynamic actin-based protrusions	Mus musculus	16020	-
membrane	association of brain-type creatine kinase with membrane structures such as synaptic vesicles and mitochondria, involving hydrophobic and electrostatic interactions, respectively. Membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations. Recruitment of BCK to submembrane domains also supports formation of dynamic actin-based protrusions. Hypothetical model of BCK localization at cellular membranes, overview	Rattus norvegicus	16020	-
mitochondrial inner membrane	-	Mus musculus	5743	-
mitochondrial outer membrane	-	Mus musculus	5741	-
mitochondrion	-	Rattus norvegicus	5739	-
mitochondrion	association with by brain-type creatine kinase	Mus musculus	5739	-
mitochondrion	octameric MtCK is situated in the mitochondrial intermembrane space, binding simultaneously to both mitochondrial inner and outer membranes, as well as in the cristae space bound to inner membrane	Mus musculus	5739	-
additional information	as compared to total, mainly soluble brain BCK, the BCK bound to mitochondria and synaptic vesicles appears to be heterogeneous. Appreciable amounts of cytosolic BCK are bound to synaptic vesicles and mitochondrial membranes, and these interactions are governed by different mechanisms and possibly linked to secondary BCK modifications. Two different mechanisms are possible involving either the membrane or the BCK binding partner: (1) A specific mitochondrial receptor is required, which is absent in liver and removed by the high pH treatment in brain, or (2) BCK requires posttranslational modifications which are missing on the recombinant enzyme	Rattus norvegicus	-	-
additional information	the BCK isoform is mostly soluble but partially associates with cellular structures, subcellular localizations and cellular interaction partners of BCK, overview	Mus musculus	-	-
additional information	the mitochondrial enzyme participates in large complexes that include the voltage-dependent anion channel in the mitochondrial outer membrane as well as cardiolipin and adenine nucleotide transporter in the mitochondrial inner membrane, localization and complex formation of MtCK, overview	Mus musculus	-	-
nucleus	-	Mus musculus	5634	-
plasma membrane	-	Mus musculus	5886	-
synaptic vesicle	association with by brain-type creatine kinase	Mus musculus	8021	-
synaptic vesicle	association with by brain-type creatine kinase, isolated from rat forebrains by separation from nerve-ending particles (synaptosomes). Synaptic vesicle BCK is indeed firmly anchored in the vesicle membrane and not just interacting electrostatically with the lipid headgroups or simply enclosed within the vesicles	Rattus norvegicus	8021	-
synaptosome	-	Rattus norvegicus	-	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Mus musculus
Mg2+	required	Rattus norvegicus

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.
ATP + creatine	Mus musculus	-	ADP + phosphocreatine	-	r
ATP + creatine	Rattus norvegicus	-	ADP + phosphocreatine	-	r
ATP + creatine	Mus musculus	the mitochondrial isozyme MtCK catalyzes the almost complete transphosphorylation of mitochondrial ATP and cytosolic creatine into ADP and phophocreatine. ADP locally generated by MtCK is transferred into the matrix for rephosphorylation and phosphocreatine is released from mitochondria into the cytosol, direct channelling of ATP and ADP between mitochondrial matrix and MtCK via adenine nucleotide transporter	ADP + phosphocreatine	-	r
ATP + creatine	Rattus norvegicus Wistar	-	ADP + phosphocreatine	-	r
additional information	Mus musculus	membrane proteins VAMP2/3 and JWA are putative BCK interaction partners. At the plasma membrane, BCK interacts with at least two members of the family of cation-coupled chloride transporters (solute carrier family 12): the K+/Cl- cotransporters 2 (KCC2 or SLC12A5) and 3 (KCC3 or SLC12A6), BCK may be required for maximal phosphorylation efficiency	?	-	?
additional information	Rattus norvegicus	synaptical vesicle protein VAMP2/3 and membrane protein and JWA are BCK interaction partners, by Y2H assays. VAMP3 interacts with both, wild-type BCK and truncated DELTABCK mutant. The common and characteristic SNARE domain of VAMPs (amino acids 14-74 in VAMP3) is not sufficient for BCK interaction. JWA and VAMP both link BCK to energy-requiring intracellular vesicle transport	?	-	?
additional information	Rattus norvegicus Wistar	synaptical vesicle protein VAMP2/3 and membrane protein and JWA are BCK interaction partners, by Y2H assays. VAMP3 interacts with both, wild-type BCK and truncated DELTABCK mutant. The common and characteristic SNARE domain of VAMPs (amino acids 14-74 in VAMP3) is not sufficient for BCK interaction. JWA and VAMP both link BCK to energy-requiring intracellular vesicle transport	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Mus musculus	P30275	U-type creatine kinase; gene Ckmt1	-
Mus musculus	Q04447	B-type creatine kinase; gene Ckb	-
Rattus norvegicus	P07335	B-type creatine kinase; gene Ckb	-
Rattus norvegicus Wistar	P07335	B-type creatine kinase; gene Ckb	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
phosphoprotein	the cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate brain-type cratine kinase at Ser6 to trigger the enzyme's localization at the endoplasmic reticulum, in close vicinity of the highly energy-demanding Ca2+ ATPase pump	Mus musculus
phosphoprotein	the cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate brain-type cratine kinase at Ser6 to trigger the enzyme's localization at the endoplasmic reticulum, in close vicinity of the highly energy-demanding Ca2+ ATPase pump. BCK phosphorylation is a regulatory process for cellular localization that involves a particular physiological signal (energy stress) which is highly specific for a defined protein kinase (AMPK) and a specific BCK site (Ser6), and provides colocalization between BCK and an ATPase	Rattus norvegicus

Purification (Commentary)

Purification (Comment)	Organism
native isozyme BCK in synaptic vesicles and membranes of neuronal synaptosomes and mitochondria	Rattus norvegicus

Source Tissue

Source Tissue	Comment	Organism	Textmining
astrocyte	-	Mus musculus	-
brain	-	Rattus norvegicus	-
brain	cytosolic brain-type cratine kinase	Mus musculus	-
brain	cytosolic brain-type creatine kinase, the CK energy buffering and shuttle system seems to operate in many brain cells, in particular in the polarized large cells like neurons or hair bundle and photoreceptor cells in the sensory organs	Mus musculus	-
fibroblast	-	Mus musculus	-
forebrain	-	Rattus norvegicus	-
additional information	in a given cell type, at least one dimeric cytosolic isoform is always co-expressed with a predominantly octameric mitochondrial isoform (MtCK), generally cytosolic muscle-type CK (MCK) with sarcomeric MtCK (sMtCK), or cytosolic brain-type CK (BCK) with ubiquitous MtCK	Mus musculus	-
additional information	no expression of BCK in liver	Rattus norvegicus	-
myotube	in cultured mouse myotubes, BCK localizes near the endings of the cells, interaction with skeletal and cardiac alpha-actin	Mus musculus	-
photoreceptor cell	-	Mus musculus	-
retina	-	Mus musculus	-
stomach	parietal cells of the stomach, BCK is co-localizing with and fueling the gastric H+/K+-ATPase pump at the apical membrane and the membranes of the tubulovesicular system	Mus musculus	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
ATP + creatine	-	Mus musculus	ADP + phosphocreatine	-	r
ATP + creatine	-	Rattus norvegicus	ADP + phosphocreatine	-	r
ATP + creatine	the mitochondrial isozyme MtCK catalyzes the almost complete transphosphorylation of mitochondrial ATP and cytosolic creatine into ADP and phophocreatine. ADP locally generated by MtCK is transferred into the matrix for rephosphorylation and phosphocreatine is released from mitochondria into the cytosol, direct channelling of ATP and ADP between mitochondrial matrix and MtCK via adenine nucleotide transporter	Mus musculus	ADP + phosphocreatine	-	r
ATP + creatine	-	Rattus norvegicus Wistar	ADP + phosphocreatine	-	r
additional information	membrane proteins VAMP2/3 and JWA are putative BCK interaction partners. At the plasma membrane, BCK interacts with at least two members of the family of cation-coupled chloride transporters (solute carrier family 12): the K+/Cl- cotransporters 2 (KCC2 or SLC12A5) and 3 (KCC3 or SLC12A6), BCK may be required for maximal phosphorylation efficiency	Mus musculus	?	-	?
additional information	synaptical vesicle protein VAMP2/3 and membrane protein and JWA are BCK interaction partners, by Y2H assays. VAMP3 interacts with both, wild-type BCK and truncated DELTABCK mutant. The common and characteristic SNARE domain of VAMPs (amino acids 14-74 in VAMP3) is not sufficient for BCK interaction. JWA and VAMP both link BCK to energy-requiring intracellular vesicle transport	Rattus norvegicus	?	-	?
additional information	synaptical vesicle protein VAMP2/3 and membrane protein and JWA are BCK interaction partners, by Y2H assays. VAMP3 interacts with both, wild-type BCK and truncated DELTABCK mutant. The common and characteristic SNARE domain of VAMPs (amino acids 14-74 in VAMP3) is not sufficient for BCK interaction. JWA and VAMP both link BCK to energy-requiring intracellular vesicle transport	Rattus norvegicus Wistar	?	-	?

Subunits

Subunits	Comment	Organism
dimer	cytosolic isozyme	Mus musculus
octamer	mitochondrial isozyme	Mus musculus
octamer	mitochondrial isozyme	Rattus norvegicus

Synonyms

Synonyms	Comment	Organism
B-type creatine kinase	-	Mus musculus
B-type creatine kinase	-	Rattus norvegicus
BCK	-	Mus musculus
BCK	-	Rattus norvegicus
brain-type CK	-	Mus musculus
brain-type CK	-	Rattus norvegicus
ckb	-	Rattus norvegicus
mitochondrial creatine kinase	-	Mus musculus
MtCK	-	Mus musculus
ubiquitous MtCK	-	Mus musculus
uMtCK	-	Mus musculus

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
37	-	assay at	Rattus norvegicus

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.4	11.5	assay at	Rattus norvegicus

Cofactor

Cofactor	Comment	Organism
ADP	-	Mus musculus
ADP	-	Rattus norvegicus
ATP	-	Mus musculus
ATP	-	Rattus norvegicus

General Information

General Information	Comment	Organism
malfunction	knockout mice that lack the brain CK isoforms, i.e. BCK and/or ubiquitous MtCK, uMtCK, show defects in spatial memory acquisition and behavior, development of the hippocampus, correct functioning of hair bundle cells in the auditory system, and energy distribution within photoreceptor cells, transgenic models of creatine deficiency, overview	Mus musculus
metabolism	co-localization and functional coupling of creatine kinase isoforms with ATP-producing and ATP-consuming reactions, a non-equilibrium state of the creatine kinase reaction, and restricted intracellular diffusion of adenine nucleotides support the concept of a cellular CK/PCr phosphoryl transfer network. spatial organization of the CK/PCr shuttle in brain, in particular the association of BCK to subcellular components as well as to specific, interacting proteins, overview	Rattus norvegicus
metabolism	co-localization and functional coupling of creatine kinase isoforms with ATP-producing and ATP-consuming reactions, a non-equilibrium state of the creatine kinase reaction, and restricted intracellular diffusion of adenine nucleotides support the concept of a cellular CK/PCr phosphoryl transfer network. The reactions catalyzed by different isoforms of compartmentalized creatine kinase, organized in intracellular energetic units tend to maintain the intracellular metabolic stability	Mus musculus
metabolism	importance of functional coupling between MtCK, ANT and respiration/ATP synthesis provided by the close co-localization of MtCK and ANT in proteolipid complexes. Co-localization and functional coupling of creatine kinase isoforms with ATP-producing and ATP-consuming reactions, a non-equilibrium state of the creatine kinase reaction, and restricted intracellular diffusion of adenine nucleotides support the concept of a cellular CK/PCr phosphoryl transfer network. The reactions catalyzed by different isoforms of compartmentalized creatine kinase, organized in intracellular energetic units tend to maintain the intracellular metabolic stability	Mus musculus
additional information	phosphocreatine is an alternative energy carrier that compared to ATP is metabolically inert (except for the creatine kinase reaction), much smaller in molecular size and less charged over the physiological pH range, and is thus significantly more diffusible than ATP	Mus musculus
additional information	phosphocreatine is an alternative energy carrier that compared to ATP is metabolically inert (except for the creatine kinase reaction), much smaller in molecular size and less charged over the physiological pH range, and is thus significantly more diffusible than ATP	Rattus norvegicus
physiological function	creatine kinase is a key player in maintaining cellular energy homeostasis using creatine for reversible phosphoryl transfer between ATP and phosphocreatine. The cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate brain-type cratine kinase at Ser6 to trigger BCK localization at the endoplasmic reticulum, in close vicinity of the highly energy-demanding Ca2+ ATPase pump. Recruitment of BCK into the surface layer of a membrane, close to ATPases, and the resulting two-dimensional ATP diffusion along the membrane are sufficient to provide an energetic advantage. BCK may fuel the endoplasmic reticulum Ca2+ ATPase pump	Rattus norvegicus
physiological function	creatine kinase is a key player in maintaining cellular energy homeostasis using creatine for reversible phosphoryl transfer between ATP and phosphocreatine. The cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate brain-type cratine kinase at serine 6 to trigger BCK localization at the endoplasmic reticulum, in close vicinity of the highly energy-demanding Ca2+ ATPase pump. Membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations. Creatine kinase microcompartments play a role in the energy metabolism. At the cellular level, creatine kinase acts mainly via two different mechanisms. Firstly, the enzyme enables the building-up of a global cellular energy buffer in the form of a large phosphocreatine pool that can be used to regenerate ATP during a temporal mismatch between ATP generation and consumption. Secondly, cytosolic and mitochondrial isozymes, together with highly concentrated and diffusible phosphocreatine, facilitate the so-called CK/PCr shuttle to correct for a spatial mismatch between ATP generation and -consumption within a cell. The CK/PCr shuttle is particularly important for large and polar cells with high and/or fluctuating energy demands such as skeletal and heart muscle cells, or many cell types in the brain, but may occur in any cell type expressing creatine kinase. BCK may fuel the endoplasmic reticulum Ca2+ ATPase pump. In retina photoreceptor cells, BCK may play an equally important role, but rather in synaptic transmission at the synaptic terminal or for cGMP resynthesis in the rod outer segments. In astrocytes and fibroblasts, BCK in peripheral cellular structures facilitates actin-driven cell spreading and migration	Mus musculus
physiological function	creatine kinase is a key player in maintaining cellular energy homeostasis using creatine for reversible phosphoryl transfer between ATP and phosphocreatine. The cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate brain-type cratine kinase at serine 6 to trigger BCK localization at the endoplasmic reticulum, in close vicinity of the highly energy-demanding Ca2+ ATPase pump. Membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations. Creatine kinase microcompartments play a role in the energy metabolism. At the cellular level, creatine kinase acts mainly via two different mechanisms. Firstly, the enzyme enables the building-up of a global cellular energy buffer in the form of a large phosphocreatine pool that can be used to regenerate ATP during a temporal mismatch between ATP generation and consumption. Secondly, cytosolic and mitochondrial isozymes, together with highly concentrated and diffusible phosphocreatine, facilitate the so-called CK/PCr shuttle to correct for a spatial mismatch between ATP generation and -consumption within a cell. The CK/PCr shuttle is particularly important for large and polar cells with high and/or fluctuating energy demands such as skeletal and heart muscle cells, or many cell types in the brain, but may occur in any cell type expressing creatine kinase. The role of MtCK within the mitochondrial interactosome is to separate energy fluxes from the intracellular energy signals and to amplify these signals due to the intramitochondrial recycling of ADP	Mus musculus