Literature summary for 2.7.1.137 extracted from

Voss, O.H.; Gillespie, J.J.; Lehman, S.S.; Rennoll, S.A.; Beier-Sexton, M.; Rahman, M.S.; Azad, A.F.
Risk1, a phosphatidylinositol 3-kinase effector, promotes Rickettsia typhi intracellular survival (2020), mBio, 11, e00820-20 .

Search for more literature for 2.7.1.137

Cloned(Commentary)

Cloned (Comment)	Organism
gene RT1035, recombinant expression of wild-type and mutant enzymes in HeLa cells	Rickettsia typhi

Protein Variants

Protein Variants	Comment	Organism
H297A	site-directed mutagenesis, a kinase dead mutant. Overexpression of Risk1 H297A results in a significant reduction in colocalization with all tested PI sensors. Cells transfected with Risk1 H297A display a significant increase in apoptosis	Rickettsia typhi

Inhibitors

Inhibitors	Comment	Organism	Structure
1-([2-[(2-chloropyridin-4-yl)amino]-4'-(cyclopropylmethyl)[4,5'-bipyrimidin]-2'-yl]amino)-2-methylpropan-2-ol	Vpsn34-IN1	Rickettsia typhi
proteinase K	proteinase K treatment of partially purified Rickettsia typhi results in a dose-dependent degradation of Risk1 on the bacterial membrane	Rickettsia typhi

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
additional information	the enzyme is secreted intracellularly in the host cell by Rickettsia typhi. Risk1 is present in both the pellet and supernatant of infected cells, implying that Risk1 is secreted into the host cell cytoplasm. Risk1 and Rab5 or EEA1 colocalization	Rickettsia typhi	-	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Rickettsia typhi

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
ATP + 1-phosphatidyl-1D-myo-inositol	Rickettsia typhi	-	ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate	-	?
ATP + 1-phosphatidyl-1D-myo-inositol	Rickettsia typhi ATCC VR-144	-	ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate	-	?
ATP + 1-phosphatidyl-1D-myo-inositol	Rickettsia typhi Wilmington	-	ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate	-	?

Organism

Organism	UniProt	Comment	Textmining
Rickettsia typhi	Q68XM2	progressed in Vero 76 cells	-
Rickettsia typhi ATCC VR-144	Q68XM2	progressed in Vero 76 cells	-
Rickettsia typhi Wilmington	Q68XM2	progressed in Vero 76 cells	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
additional information	proteinase K treatment of partially purified Rickettsia typhi results in a dose-dependent degradation of Risk1 on the bacterial membrane	Rickettsia typhi

Source Tissue

Source Tissue	Comment	Organism	Textmining
additional information	the enzyme is secreted intracellularly in the host cell by Rickettsia typhi. Risk1 is present in both the pellet and supernatant of infected cells, implying that Risk1 is secreted into the host cell cytoplasm. Risk1 is deposited on the rickettsial cell surface after translocation through the secretion channel and is delivered into the host cell environment during Rickettsia typhi infection. Strong colocalization is observed between wild-type Risk1 and the tagged biosensors for PI(3)P, PI(3,4,5)P3, PI(3,4)P2, and PI(4,5)P2 in host cells	Rickettsia typhi	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + 1-phosphatidyl-1D-myo-inositol	-	Rickettsia typhi	ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate	-	?
ATP + 1-phosphatidyl-1D-myo-inositol	-	Rickettsia typhi ATCC VR-144	ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate	-	?
ATP + 1-phosphatidyl-1D-myo-inositol	-	Rickettsia typhi Wilmington	ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate	-	?
additional information	wild-type Risk1 binds preferentially to PIs (i.e., phosphatidylinositol [PI], phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and phosphatidylserine [PS]) over other lipids such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), diacylglycerol (DAG), cholesterol, or sphingomyelin. Class III PI3Ks convert PI to phosphatidylinositol 3-phosphate [PI(3)P]	Rickettsia typhi	?	-	-
additional information	wild-type Risk1 binds preferentially to PIs (i.e., phosphatidylinositol [PI], phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and phosphatidylserine [PS]) over other lipids such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), diacylglycerol (DAG), cholesterol, or sphingomyelin. Class III PI3Ks convert PI to phosphatidylinositol 3-phosphate [PI(3)P]	Rickettsia typhi ATCC VR-144	?	-	-
additional information	wild-type Risk1 binds preferentially to PIs (i.e., phosphatidylinositol [PI], phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], and phosphatidylserine [PS]) over other lipids such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), diacylglycerol (DAG), cholesterol, or sphingomyelin. Class III PI3Ks convert PI to phosphatidylinositol 3-phosphate [PI(3)P]	Rickettsia typhi Wilmington	?	-	-

Subunits

Subunits	Comment	Organism
?	x * 81000, native enzyme, SDS-PAGE, x * 82000, recombinant codon-optimized enzyme, SDS-PAGE	Rickettsia typhi

Synonyms

Synonyms	Comment	Organism
phosphatidylinositol 3-kinase	-	Rickettsia typhi
PI3K	-	Rickettsia typhi
Rickettsia intracellular secreted kinase-1	-	Rickettsia typhi
Risk1	-	Rickettsia typhi
RT0135	-	Rickettsia typhi

Cofactor

Cofactor	Comment	Organism	Structure
ATP	-	Rickettsia typhi

General Information

General Information	Comment	Organism
evolution	RT0135 contains conserved residues within the catalytic and activation loops of the diverse PI3/PI4 family effectors	Rickettsia typhi
malfunction	pretreatment of Rickettsia with Risk1-specific antibody for various lengths of time shows that neutralization of Risk1 significantly reduces Rickettsia typhi internalization, which is consequently resulting in an increase in bacterial adherence. In contrast, pretreatment of Rickettsia typhi with an alphaIgG isotype control Ab shows no reduction in bacterial internalization, indicating that the reduction in Rickettsia typhi infectivity is the result of direct inhibition of Risk1 functionality and not due to steric hindrance induced by the Fc portion of the alphaRisk1 Ab. Cells overexpressing wild-type Risk1 have an about 2.5fold higher bacterial burden than cells expressing either vector or Risk1 H297A mutant. Inhibition of PI3K activity negatively affects Rickettsia typhi internalization and the colocalization of Risk1 with Rab5 and EEA. Cells transfected with Risk1 H297A display a significant increase in apoptosis1	Rickettsia typhi
metabolism	no association between Beclin-1 and Risk1 or Bcl-2 is observed after prolonged Rickettsia typhi infection	Rickettsia typhi
physiological function	Risk1 is a phosphatidylinositol 3-kinase (PI3K) and a secreted effector involved in Rickettsia typhi host cell invasion, a T4SS effector, and the first bacterial secretory kinase with both class I and III PI3K activities. The rickettsial effector phosphatidylinositol 3-kinase (PI3K) has a dual specificity for phosphoinositides. Risk1 is a phosphatidylinositol 3-kinase with class I and III activities critical for Rickettsia typhi invasion. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. binding to Rab5 requires the kinase activity of Risk1. Subsequently, Rickettsia typhi undergoes ubiquitination and induces host autophagy. Maturation to autolysosomes is subverted to support intracellular growth. Only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to Rickettsia typhi-induced autophagosome formation. Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of Rickettsia typhi. Risk1 targets endosomal trafficking and Rickettsia typhi-induced autophagy to promote intracellular growth. Risk1, via its kinase activity, contributes to a nonapoptotic cell rounding phenotype	Rickettsia typhi

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Release 2023.1 (January 2023)