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NMR structure of the N-SH2 of the p85 subunit of phosphoinositide 3-kinase complexed to a doubly phosphorylated peptide reveals a second phosphotyrosine binding site.

Weber T, Schaffhausen B, Liu Y, Günther UL
Biochemistry 39 15860-9 (2000)
Cited: 21 times
EuropePMC logo PMID: 11123912

Abstract

The N-terminal src homology 2 (SH2) domain of the p85 subunit of phosphoinositide 3-kinase (PI3K) has a higher affinity for a peptide with two phosphotyrosines than for the same peptide with only one. This unexpected result was not observed for the C-terminal SH2 from the same protein. NMR structural analysis has been used to understand the behavior of the N-SH2. The structure of the free SH2 domain has been compared to that of the SH2 complexed with a doubly phosphorylated peptide derived from polyomavirus middle T antigen (MT). The structure of the free SH2 domain shows some differences from previous NMR and X-ray structures. In the N-SH2 complexed with a doubly phosphorylated peptide, a second site for phosphotyrosine interaction has been identified. Further, line shapes of NMR signals showed that the SH2 protein-ligand complex is subject to temperature-dependent conformational mobility. Conformational mobility is also supported by the spectra of the ligand peptide. A binding model which accounts for these results is developed.

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Reviews citing this publication (4)

  1. Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases. Djordjevic S, Driscoll PC. Trends Biochem Sci 27 426-432 (2002)
  2. NMRKIN: simulating line shapes from two-dimensional spectra of proteins upon ligand binding. Günther UL, Schaffhausen B. J Biomol NMR 22 201-209 (2002)
  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)
  4. The Importance of Being PI3K in the RAS Signaling Network. Cuesta C, Arévalo-Alameda C, Castellano E. Genes (Basel) 12 (2021)

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  1. Mechanism of constitutive phosphoinositide 3-kinase activation by oncogenic mutants of the p85 regulatory subunit. Shekar SC, Wu H, Fu Z, Yip SC, Nagajyothi, Cahill SM, Girvin ME, Backer JM. J Biol Chem 280 27850-27855 (2005)
  2. Structural basis for the requirement of two phosphotyrosine residues in signaling mediated by Syk tyrosine kinase. Groesch TD, Zhou F, Mattila S, Geahlen RL, Post CB. J Mol Biol 356 1222-1236 (2006)
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  4. Alterations in gene expression profiles and the DNA-damage response in ionizing radiation-exposed TK6 cells. Akerman GS, Rosenzweig BA, Domon OE, Tsai CA, Bishop ME, McGarrity LJ, Macgregor JT, Sistare FD, Chen JJ, Morris SM. Environ Mol Mutagen 45 188-205 (2005)
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  6. Novel mechanism of interaction of p85 subunit of phosphatidylinositol 3-kinase and ErbB3 receptor-derived phosphotyrosyl peptides. Suenaga A, Takada N, Hatakeyama M, Ichikawa M, Yu X, Tomii K, Okimoto N, Futatsugi N, Narumi T, Shirouzu M, Yokoyama S, Konagaya A, Taiji M. J Biol Chem 280 1321-1326 (2005)
  7. Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation. Porter CJ, Matthews JM, Mackay JP, Pursglove SE, Schmidberger JW, Leedman PJ, Pero SC, Krag DN, Wilce MC, Wilce JA. BMC Struct Biol 7 58 (2007)
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  10. The iSH2 domain of PI 3-kinase is a rigid tether for p110 and not a conformational switch. Fu Z, Aronoff-Spencer E, Wu H, Gerfen GJ, Backer JM. Arch Biochem Biophys 432 244-251 (2004)
  11. Single phosphorylation of Tyr304 in the cytoplasmic tail of ephrin B2 confers high-affinity and bifunctional binding to both the SH2 domain of Grb4 and the PDZ domain of the PDZ-RGS3 protein. Su Z, Xu P, Ni F. Eur J Biochem 271 1725-1736 (2004)
  12. Structural and thermodynamic basis for the interaction of the Src SH2 domain with the activated form of the PDGF beta-receptor. Lubman OY, Waksman G. J Mol Biol 328 655-668 (2003)
  13. Computational Insights into the Interactions between Calmodulin and the c/nSH2 Domains of p85α Regulatory Subunit of PI3Kα: Implication for PI3Kα Activation by Calmodulin. Ni D, Liu D, Zhang J, Lu S. Int J Mol Sci 19 (2018)
  14. Hierarchy of simulation models in predicting molecular recognition mechanisms from the binding energy landscapes: structural analysis of the peptide complexes with SH2 domains. Verkhivker GM, Bouzida D, Gehlhaar DK, Rejto PA, Schaffer L, Arthurs S, Colson AB, Freer ST, Larson V, Luty BA, Marrone T, Rose PW. Proteins 45 456-470 (2001)
  15. Two phosphorylation-independent sites on the p85 SH2 domains bind A-Raf kinase. Fang Y, Johnson LM, Mahon ES, Anderson DH. Biochem Biophys Res Commun 290 1267-1274 (2002)
  16. Cryo-EM structures of PI3Kα 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 118 (2021)


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