| 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
During T-cell regulation, T-cell receptors and CD28 lead to signaling activation, while T-lymphocyte antigen 4 (CTLA-4) is known to lead to downregulation, similar to programmed cell death-1 (PD-1). In the cytoplasmic tails of CD28 and CTLA-4, phosphoinositide 3-kinase (PI3K) binds to the consensus sequence including phosphotyrosine via SH2 domains, N- and C-terminal SH2 domains (nSH2 and cSH2), of its regulatory subunit, p85. In this study, we determined the crystal structure of a CTLA-4-derived phosphopeptide in complex with a Cys-substituted mutant of cSH2, C656S/C659V/C670L, at a 1.1 A resolution. Phosphotyrosine of the bound peptide is tightly accommodated by the residues Arg631, Arg649, Ser651, and Ser652, similar to the cSH2 wild-type recognition mode of CD28, as reported previously. Upon the Cys mutation, the cSH2 thermal stability increased while the CTLA-4 binding affinity slightly changed. The binding experiments also showed that the binding affinity of CTLA-4 by cSH2 was approximately two orders of magnitude lower than that of CD28. Similar to CD28 binding, the CTLA-4 binding affinity of nSH2 was lower than that of cSH2. The complex structure of nSH2 and CTLA-4 was modeled, and compared with the crystal structure of cSH2 mutant and CTLA-4. The difference in the binding affinity between CD28 and CTLA-4, along with the difference between nSH2 and cSH2, could be explained by the 3D structures, which would be closely correlated with the respective T-cell signaling.
Molecular interactions of the CTLA-4 cytoplasmic region with the phosphoinositide 3-kinase SH2 domains.,Iiyama M, Numoto N, Ogawa S, Kuroda M, Morii H, Abe R, Ito N, Oda M Mol Immunol. 2021 Mar;131:51-59. doi: 10.1016/j.molimm.2020.12.002. Epub 2020 Dec , 30. PMID:33386150[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
- ↑ Iiyama M, Numoto N, Ogawa S, Kuroda M, Morii H, Abe R, Ito N, Oda M. Molecular interactions of the CTLA-4 cytoplasmic region with the phosphoinositide 3-kinase SH2 domains. Mol Immunol. 2021 Mar;131:51-59. PMID:33386150 doi:10.1016/j.molimm.2020.12.002
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