1h10: Difference between revisions
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==Overview== | ==Overview== | ||
The products of PI 3-kinase activation, PtdIns(3,4,5)P3 and its immediate, breakdown product PtdIns(3,4)P2, trigger physiological processes, by, interacting with proteins possessing pleckstrin homology (PH) domains. One, of the best characterized PtdIns(3,4,5)P3/PtdIns(3,4)P2 effector proteins, is protein kinase B (PKB), also known as Akt. PKB possesses a PH domain, located at its N terminus, and this domain binds specifically to, PtdIns(3,4,5)P3 and PtdIns(3,4)P2 with similar affinity. Following, activation of PI 3-kinase, PKB is recruited to the plasma membrane by, virtue of its interaction with PtdIns(3,4,5)P3/PtdIns(3,4)P2. PKB is then, activated by the 3-phosphoinositide-dependent pro-tein kinase-1 (PDK1), which like PKB, possesses a PtdIns(3,4,5)P3/PtdIns(3,4)P2 binding PH, domain. Here, we describe the high-resolution crystal structure of the, isolated PH domain of PKB(alpha) in complex with the head group of, PtdIns(3,4,5)P3. The head group has a significantly different orientation, and location compared to other Ins(1,3,4,5)P4 binding PH domains., Mutagenesis of the basic residues that form ionic interactions with the D3, and D4 phosphate groups reduces or abolishes the ability of PKB to, interact with PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The D5 phosphate faces, the solvent and forms no significant interactions with any residue on the, PH domain, and this explains why PKB interacts with similar affinity with, both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. | The products of PI 3-kinase activation, PtdIns(3,4,5)P3 and its immediate, breakdown product PtdIns(3,4)P2, trigger physiological processes, by, interacting with proteins possessing pleckstrin homology (PH) domains. One, of the best characterized PtdIns(3,4,5)P3/PtdIns(3,4)P2 effector proteins, is protein kinase B (PKB), also known as Akt. PKB possesses a PH domain, located at its N terminus, and this domain binds specifically to, PtdIns(3,4,5)P3 and PtdIns(3,4)P2 with similar affinity. Following, activation of PI 3-kinase, PKB is recruited to the plasma membrane by, virtue of its interaction with PtdIns(3,4,5)P3/PtdIns(3,4)P2. PKB is then, activated by the 3-phosphoinositide-dependent pro-tein kinase-1 (PDK1), which like PKB, possesses a PtdIns(3,4,5)P3/PtdIns(3,4)P2 binding PH, domain. Here, we describe the high-resolution crystal structure of the, isolated PH domain of PKB(alpha) in complex with the head group of, PtdIns(3,4,5)P3. The head group has a significantly different orientation, and location compared to other Ins(1,3,4,5)P4 binding PH domains., Mutagenesis of the basic residues that form ionic interactions with the D3, and D4 phosphate groups reduces or abolishes the ability of PKB to, interact with PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The D5 phosphate faces, the solvent and forms no significant interactions with any residue on the, PH domain, and this explains why PKB interacts with similar affinity with, both PtdIns(3,4,5)P3 and PtdIns(3,4)P2. | ||
==Disease== | |||
Known diseases associated with this structure: Neutrophil immunodeficiency syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602049 602049]], Schizophrenia, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164730 164730]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:11:22 2007'' | ||
