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|3pxd, resolution 2.80Å ()|
|Gene:||BRCA1, RNF53 (Homo sapiens)|
|Related:||1t2v, 1t15, 1n5o, 1t2u, 2ing, 3pxa, 3pxb, 3pxc, 3pxe|
Impact of BRCA1 BRCT domain missense substitutions on phospho-peptide recognition: R1835P
The BRCA1 BRCT domain binds pSer-x-x-Phe motifs in partner proteins to regulate the cellular response to DNA damage. Approximately 120 distinct missense variants have been identified in the BRCA1 BRCT through breast cancer screening, and several of these have been linked to an in-creased cancer risk. Here we probe the structures and peptide-binding activities of variants that affect the BRCA1 BRCT phospho-peptide-binding groove. The results obtained from the G1656D and T1700A variants illustrate the role of Ser1655 in pSer recognition. Mutations at Arg1699 (R1699W and R1699Q) significantly reduce peptide binding, through loss of contacts to the main chain of the Phe (+3) residue, and, in the case of R1699W, to a destabilization of the BRCT fold. The R1835P and E1836K variants do not dramatically reduce peptide binding, in spite of the fact that these mutations sig-nificantly alter the structure of the walls of the Phe (+3) pocket.
Impact of BRCA1 BRCT domain missense substitutions on phospho-peptide recognition., Coquelle N, Green R, Glover JN, Biochemistry. 2011 Apr 7. PMID:21473589
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Coquelle N, Green R, Glover JN. Impact of BRCA1 BRCT domain missense substitutions on phospho-peptide recognition. Biochemistry. 2011 Apr 7. PMID:21473589 doi:10.1021/bi2003795
- Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, Hui B, Monteiro AN, Glover JN. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res. 2010 Jun 15;70(12):4880-90. Epub 2010 Jun 1. PMID:20516115 doi:10.1158/0008-5472.CAN-09-4563
- Williams RS, Lee MS, Hau DD, Glover JN. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nat Struct Mol Biol. 2004 Jun;11(6):519-25. Epub 2004 May 9. PMID:15133503 doi:10.1038/nsmb776
- Clapperton JA, Manke IA, Lowery DM, Ho T, Haire LF, Yaffe MB, Smerdon SJ. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol. 2004 Jun;11(6):512-8. Epub 2004 May 9. PMID:15133502 doi:10.1038/nsmb775
- Williams RS, Glover JN. Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J Biol Chem. 2003 Jan 24;278(4):2630-5. Epub 2002 Nov 8. PMID:12427738 doi:10.1074/jbc.M210019200