| Structural highlights
Function
P85A_HUMAN Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.[1] [2] [3]
Publication Abstract from PubMed
Phosphoinositide 3-kinases (PI3Ks) are lipid kinases essential for growth and metabolism. Their aberrant activation is associated with many types of cancers. Here we used single-particle cryoelectron microscopy (cryo-EM) to determine three distinct conformations of full-length PI3Kalpha (p110alpha-p85alpha): the unliganded heterodimer PI3Kalpha, PI3Kalpha bound to the p110alpha-specific inhibitor BYL-719, and PI3Kalpha exposed to an activating phosphopeptide. The cryo-EM structures of unbound and of BYL-719-bound PI3Kalpha are in general accord with published crystal structures. Local deviations are presented and discussed. BYL-719 stabilizes the structure of PI3Kalpha, but three regions of low-resolution extra density remain and are provisionally assigned to the cSH2, BH, and SH3 domains of p85. One of the extra density regions is in contact with the kinase domain blocking access to the catalytic site. This conformational change indicates that the effects of BYL-719 on PI3Kalpha activity extend beyond competition with adenosine triphosphate (ATP). In unliganded PI3Kalpha, the DFG motif occurs in the "in" and "out" positions. In BYL-719-bound PI3Kalpha, only the DFG-in position, corresponding to the active conformation of the kinase, was observed. The phosphopeptide-bound structure of PI3Kalpha is composed of a stable core resolved at 3.8 A. It contains all p110alpha domains except the adaptor-binding domain (ABD). The p85alpha domains, linked to the core through the ABD, are no longer resolved, implying that the phosphopeptide activates PI3Kalpha by fully releasing the niSH2 domain from binding to p110alpha. The structures presented here show the basal form of the full-length PI3Kalpha dimer and document conformational changes related to the activated and inhibited states.
Cryo-EM structures of PI3Kalpha reveal conformational changes during inhibition and activation.,Liu X, Yang S, Hart JR, Xu Y, Zou X, Zhang H, Zhou Q, Xia T, Zhang Y, Yang D, Wang MW, Vogt PK Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2109327118. doi: , 10.1073/pnas.2109327118. PMID:34725156[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vainikka S, Joukov V, Wennstrom S, Bergman M, Pelicci PG, Alitalo K. Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. J Biol Chem. 1994 Jul 15;269(28):18320-6. PMID:7518429
- ↑ Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007 Jul 13;317(5835):239-42. PMID:17626883 doi:317/5835/239
- ↑ Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):16996-7001. Epub 2009 Sep 23. PMID:19805105
- ↑ Liu X, Yang S, Hart JR, Xu Y, Zou X, Zhang H, Zhou Q, Xia T, Zhang Y, Yang D, Wang MW, Vogt PK. Cryo-EM structures of PI3Kα reveal conformational changes during inhibition and activation. Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2109327118. PMID:34725156 doi:10.1073/pnas.2109327118
|
