Structural Insights into the Association between BCAR3 and Cas Family Members, an Atypical Complex Implicated in Anti-Oestrogen Resistance |
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Authors: | Marie-Line Garron,Diana Arsenieva,Jessie Zhong,Alexander B. Bloom,Geraldine M. O&rsquo Neill,Stefan T. Arold |
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Affiliation: | 1 INSERM, U554, 34090 Montpellier, France 2 CNRS, UMR5048, Centre de Biochimie Structurale, 2, 34090 Montpellier, France 3 Universités Montpellier 1 and 2, 34090 Montpellier, France 4 Focal Adhesion Biology Group, The Oncology Research Unit, The Children's Hospital at Westmead, New South Wales 2145, Australia 5 Discipline of Paediatrics and Child Health, University of Sydney, Westmead, New South Wales 2006, Australia 6 Department of Medicine, Section of Hematology and Oncology, Boston University Medical School, Boston, MA 02118, USA |
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Abstract: | 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. |
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Keywords: | NSP, novel SH2-containing protein Cas, Crk-associated substrate BCAR3, breast cancer anti-oestrogen resistance 3 HEF1, human enhancer of filamentation 1 GEF, guanine nucleotide exchange factor Efs, embryonal Fyn-associated substrate FA, focal adhesion FAK, focal adhesion kinase SH2, Src homology 2 GDP, guanosine diphosphate GTPase, guanosine triphosphatase GTP, guanosine triphosphate SAXS, small-angle X-ray scattering ITC, isothermal titration calorimetry VBS, vinculin binding sequence SOS, Son of Sevenless EPAC, mouse exchange protein directly activated by cAMP REM, Ras exchanger motif HA, hemagglutinin |
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