Structural Insights into the Association between BCAR3 and Cas Family Members, an Atypical Complex Implicated in Anti-Oestrogen Resistance

Marie Line Garron, Diana Arsenieva, Jessie Zhong, Alexander B. Bloom, Adam Lerner, Geraldine M. O'Neill, Stefan T. Arold*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


The association between novel Src homology 2-containing protein (NSP) and Crk-associated substrate (Cas) family members contributes to integrin and receptor tyrosine kinase signalling and is involved in conferring anti-oestrogen resistance to human breast carcinomas. The precise role of this association in tumorigenesis remains controversial, and the molecular basis for the complex NSP and Cas protein form is unknown. Here we present a pluridisciplinary approach, including small-angle X-ray scattering, that provides first insights into the structure of the complex formed between breast cancer anti-oestrogen resistance 3 (BCAR3, an NSP family member) and human enhancer of filamentation 1 (HEF1, also named NEDD9 or Cas-L, a Cas family protein). Our analysis corroborates a four-helix bundle structure for the NSP-binding domain of HEF1 and a Cdc25-like guanine nucleotide exchange factor (GEF) fold for the Cas-binding domain of BCAR3. Using residues located on helix 2 of the four-helix bundle, HEF1 binds very tightly to a site on BCAR3 that is remote from the putative guanosine triphosphatase binding site of the GEF domain, but similar to a site implicated in allosteric regulation of the homologous SOS (Son of Sevenless) GEF domain. Thus, the association between NSP and Cas proteins might not only create a very stable link between these molecules, co-localising their cellular functions, but also modulate the function of the NSP GEF domains. Such modulation may explain, at least in part, the controversial results published for NSP GEF function.

Original languageEnglish (US)
Pages (from-to)190-203
Number of pages14
JournalJournal of molecular biology
Issue number1
StatePublished - Feb 13 2009
Externally publishedYes


  • breast cancer anti-oestrogen resistance
  • focal adhesion
  • isothermal titration calorimetry
  • protein-protein interaction
  • signal transduction

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Structural Biology


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