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Structure of a specific peptide complex of the carboxy-terminal SH2 domain from the p85 alpha subunit of phosphatidylinositol 3-kinase.

Breeze AL, Kara BV, Barratt DG, Anderson M, Smith JC, Luke RW, Best JR, Cartlidge SA
EMBO J 15 3579-89 (1996)
Cited: 34 times
EuropePMC logo PMID: 8670861

Abstract

We have determined the solution structure of the C-terminal SH2 domain of the p85 alpha subunit of human phosphatidylinositol (PI) 3-kinase (EC 2.7.1.137) in complex with a phosphorylated tyrosine pentapeptide sequence from the platelet-derived growth factor receptor using heteronuclear nuclear magnetic resonance spectroscopy. Overall, the structure is similar to other SH2 domain complexes, but displays different detail interactions within the phosphotyrosine binding site and in the recognition site for the +3 methionine residue of the peptide, the side chain of which inserts into a particularly deep and narrow pocket which is displaced relative to that of other SH2 domains. The contacts made within this +3 pocket provide the structural basis for the strong selection for methionine at this position which characterizes the SH2 domains of PI3-kinase. Comparison with spectral and structural features of the uncomplexed domain shows that the long BG loop becomes less mobile in the presence of the bound peptide. In contrast, extreme resonance broadening encountered for most residues in the beta D', beta E and beta F strands and associated connecting loops of the domain in the absence of peptide persists in the complex, implying conformational averaging in this part of the molecule on a microsecond-to-millisecond time scale.

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  3. p110α and p110β isoforms of PI3K signaling: are they two sides of the same coin? Singh P, Dar MS, Dar MJ. FEBS Lett 590 3071-3082 (2016)

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  14. Sequence, structure and energetic determinants of phosphopeptide selectivity of SH2 domains. Sheinerman FB, Al-Lazikani B, Honig B. J Mol Biol 334 823-841 (2003)
  15. Solution structure of the human Grb7-SH2 domain/erbB2 peptide complex and structural basis for Grb7 binding to ErbB2. Ivancic M, Daly RJ, Lyons BA. J Biomol NMR 27 205-219 (2003)
  16. Structural basis for the binding of high affinity phosphopeptides to Stat3. McMurray JS. Biopolymers 90 69-79 (2008)
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  18. Using a phage display library to identify basic residues in A-Raf required to mediate binding to the Src homology 2 domains of the p85 subunit of phosphatidylinositol 3'-kinase. King TR, Fang Y, Mahon ES, Anderson DH. J Biol Chem 275 36450-36456 (2000)
  19. Crystal structure of the C-terminal SH2 domain of the p85alpha regulatory subunit of phosphoinositide 3-kinase: an SH2 domain mimicking its own substrate. Hoedemaeker FJ, Siegal G, Roe SM, Driscoll PC, Abrahams JP. J Mol Biol 292 763-770 (1999)
  20. Two closely spaced tyrosines regulate NFAT signaling in B cells via Syk association with Vav. Chen CH, Martin VA, Gorenstein NM, Geahlen RL, Post CB. Mol Cell Biol 31 2984-2996 (2011)
  21. Backbone dynamics of the C-terminal SH2 domain of the p85alpha subunit of phosphoinositide 3-kinase: effect of phosphotyrosine-peptide binding and characterization of slow conformational exchange processes. Kristensen SM, Siegal G, Sankar A, Driscoll PC. J Mol Biol 299 771-788 (2000)
  22. Structural basis for SH2D1A mutations in X-linked lymphoproliferative disease. Lappalainen I, Giliani S, Franceschini R, Bonnefoy JY, Duckett C, Notarangelo LD, Vihinen M. Biochem Biophys Res Commun 269 124-130 (2000)
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  24. Conformation of an Shc-derived phosphotyrosine-containing peptide complexed with the Grb2 SH2 domain. Ogura K, Tsuchiya S, Terasawa H, Yuzawa S, Hatanaka H, Mandiyan V, Schlessinger J, Inagaki F. J Biomol NMR 10 273-278 (1997)
  25. Interaction of Calmodulin with the cSH2 Domain of the p85 Regulatory Subunit. Wang G, Zhang M, Jang H, Lu S, Lin S, Chen G, Nussinov R, Zhang J, Gaponenko V. Biochemistry 57 1917-1928 (2018)
  26. Specificity and regulation of phosphotyrosine signaling through SH2 domains. Marasco M, Carlomagno T. J Struct Biol X 4 100026 (2020)
  27. Identifying protein domains by global analysis of soluble fragment data. Bulloch EM, Kingston RL. Anal Biochem 465 53-62 (2014)


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