Literature summary for 2.7.1.153 extracted from

Echeverria, I.; Liu, Y.; Gabelli, S.; Amzel, L.
Oncogenic mutations weaken the interactions that stabilize the p110?-p85? heterodimer in phosphatidylinositol 3-kinase ?. (2015), FEBS J., 282, 3528-3542.

Search for more literature for 2.7.1.153

Activating Compound

Activating Compound	Comment	Organism	Structure
additional information	physiological activation of PI3Kalpha is triggered by binding of phosphorylated tyrosine kinase receptors RTK or their accessory proteins, such as the insulin receptor substrate 1, IRS-1, that bridge the interaction between RTK and PI3Kalpha	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
E542K/E545K	the mutation disrupts the interaction between residues E545 (helical domain) and K379 (nSH2 domain)	Homo sapiens
additional information	determination of p110alpha subunit oncogenic mutations disrupt the interactions at the p110alpha-p85alpha interface, overview. Even distant mutations (R38C/R88Q and N345K) effectively weaken the interaction between the nSH2 and helical domain, thus increasing the population of molecules that are not inhibited by the the nSH2 domain. The oncogenic mutations increase the conformational heterogeneity of the p85alpha subunit and lead to PI3Kalpha activation by releasing the p85? nSH2 inhibitory effect	Homo sapiens
N345K	the mutation significantly change the distance distribution for helical domain residues K379, I381 and K382	Homo sapiens
R38C/R88C	the mutation significantly change the distance distribution for helical domain residues K379, I381 and K382	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
additional information	in its resting state, PI3Kapha is autoinhibited by the interaction of a loop of the helical domain of p110alpha with a groove in the nSH2 domain of p85alpha. Despite this inhibition, the enzyme has a significant basal activity	Homo sapiens

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	Homo sapiens	-	ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P42336	gene PI3KCA ; gene PI3KCA	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate	-	Homo sapiens	ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate	-	?

Synonyms

Synonyms	Comment	Organism
phosphatidylinositol 3-kinase alpha	-	Homo sapiens
PI3Kalpha	-	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
ATP	-	Homo sapiens

General Information

General Information	Comment	Organism
malfunction	the PI3Kalpha signaling pathway is activated in numerous cancers, where the PI3KCA gene, which encodes for the p110alpha PI3Kalpha subunit, is mutated. Oncogenic mutations that are far from the catalytic site and increase the enzymatic affinity, destabilize the p110alpha/p85alpha dimer. By affecting the dynamics of the protein, these mutations favor the conformations that reduce the autoinhibitory effect of the p85alpha nSH2 domain. Molecular dynamics simulations suggest that all the tumor-associated mutations effectively weaken the interactions between the p110alpha and the p85alpha subunits by disrupting key stabilizing interactions	Homo sapiens
physiological function	the PI3Kalpha signaling pathway plays an important role in cell growth, proliferation and survival. This pathway is activated in numerous cancers, where the PI3KCA gene, which encodes for the p110alpha PI3Kalpha subunit, is mutated. Physiological activation of PI3Kalpha is triggered by binding of phosphorylated tyrosine kinase receptors RTK or their accessory proteins, such as the insulin receptor substrate 1, IRS-1, that bridge the interaction between RTK and PI3Kalpha	Homo sapiens

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Release 2023.1 (January 2023)