1wyx Citations

The 1.1 A resolution crystal structure of the p130cas SH3 domain and ramifications for ligand selectivity.


The Crk-associated tyrosine kinase substrate p130cas (CAS) is a docking protein containing an SH3 domain near its N terminus, followed by a short proline-rich segment, a large central substrate domain composed of 15 repeats of the four amino acid sequence YxxP, a serine-rich region and a carboxy-terminal domain, which possesses consensus binding sites for the SH2 and SH3 domains of Src (YDYV and RPLPSPP, respectively). The SH3 domain of CAS mediates its interaction with several proteins involved in signaling pathways such as focal adhesion kinase (FAK), tyrosine phosphatases PTP1B and PTP-PEST, and the guanine nucleotide exchange factor C3G. As a homolog of the corresponding Src docking domain, the CAS SH3 domain binds to proline-rich sequences (PxxP) of its interacting partners that can adopt a polyproline type II helix. We have determined a high-resolution X-ray structure of the recombinant human CAS SH3 domain. The domain, residues 1-69, crystallized in two related space groups, P2(1) and C222(1), that provided diffraction data to 1.1 A and 2.1 A, respectively. The crystal structure shows, in addition to the conserved SH3 domain architecture, the way in which the CAS characteristic amino acids form an atypically charged ligand-binding surface. This arrangement provides a rationale for the unusual ligand recognition motif exhibited by the CAS SH3 domain. The structure enables modelling of the docking interactions to its ligands, for example from focal adhesion kinase, and supports structure-based drug design of inhibitors of the CAS-FAK interaction.

Articles - 1wyx mentioned but not cited (2)

  1. SRC Homology 2 Domain Binding Sites in Insulin, IGF-1 and FGF receptor mediated signaling networks reveal an extensive potential interactome. Liu BA, Engelmann BW, Jablonowski K, Higginbotham K, Stergachis AB, Nash PD. Cell Commun. Signal 10 27 (2012)
  2. CARDIO-PRED: an in silico tool for predicting cardiovascular-disorder associated proteins. Jain P, Thukral N, Gahlot LK, Hasija Y. Syst Synth Biol 9 55-66 (2015)

Reviews citing this publication (2)

  1. CAS proteins in normal and pathological cell growth control. Tikhmyanova N, Little JL, Golemis EA. Cell. Mol. Life Sci. 67 1025-1048 (2010)
  2. Integrin signalling adaptors: not only figurants in the cancer story. Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P. Nat. Rev. Cancer 10 858-870 (2010)

Articles citing this publication (8)

  1. Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R, Tanaka S, Sheetz MP. Cell 127 1015-1026 (2006)
  2. Enteropathogenic Escherichia coli Tir is an SH2/3 ligand that recruits and activates tyrosine kinases required for pedestal formation. Bommarius B, Maxwell D, Swimm A, Leung S, Corbett A, Bornmann W, Kalman D. Mol. Microbiol. 63 1748-1768 (2007)
  3. A novel Cas family member, HEPL, regulates FAK and cell spreading. Singh MK, Dadke D, Nicolas E, Serebriiskii IG, Apostolou S, Canutescu A, Egleston BL, Golemis EA. Mol. Biol. Cell 19 1627-1636 (2008)
  4. Silencing of p130cas in ovarian carcinoma: a novel mechanism for tumor cell death. Nick AM, Stone RL, Armaiz-Pena G, Ozpolat B, Tekedereli I, Graybill WS, Landen CN, Villares G, Vivas-Mejia P, Bottsford-Miller J, Kim HS, Lee JS, Kim SM, Baggerly KA, Ram PT, Deavers MT, Coleman RL, Lopez-Berestein G, Sood AK. J. Natl. Cancer Inst. 103 1596-1612 (2011)
  5. Non-Smad transforming growth factor-β signaling regulated by focal adhesion kinase binding the p85 subunit of phosphatidylinositol 3-kinase. Hong M, Wilkes MC, Penheiter SG, Gupta SK, Edens M, Leof EB. J. Biol. Chem. 286 17841-17850 (2011)
  6. Tyrosine phosphorylation within the SH3 domain regulates CAS subcellular localization, cell migration, and invasiveness. Janoštiak R, Tolde O, Brůhová Z, Novotný M, Hanks SK, Rösel D, Brábek J. Mol. Biol. Cell 22 4256-4267 (2011)
  7. "Fuzzy oil drop" model applied to individual small proteins built of 70 amino acids. Prymula K, Sałapa K, Roterman I. J Mol Model 16 1269-1282 (2010)
  8. Structural characterization of CAS SH3 domain selectivity and regulation reveals new CAS interaction partners. Gemperle J, Hexnerová R, Lepšík M, Tesina P, Dibus M, Novotný M, Brábek J, Veverka V, Rosel D. Sci Rep 7 8057 (2017)