2ing: Difference between revisions
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caption="2ing, resolution 3.600Å" /> | caption="2ing, resolution 3.600Å" /> | ||
'''X-ray Structure of the BRCA1 BRCT mutant M1775K'''<br /> | '''X-ray Structure of the BRCA1 BRCT mutant M1775K'''<br /> | ||
==Overview== | |||
A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.European Journal of Human Genetics advance online publication, 20 February 2008; doi:10.1038/ejhg.2008.13. | |||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2ING is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CO:'>CO</scene> and <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ING OCA]. | 2ING is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CO:'>CO</scene> and <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Sites: <scene name='pdbsite=AC1:Co+Binding+Site+For+Residue+X+101'>AC1</scene>, <scene name='pdbsite=AC2:So4+Binding+Site+For+Residue+X+1'>AC2</scene> and <scene name='pdbsite=AC3:So4+Binding+Site+For+Residue+X+2'>AC3</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ING OCA]. | ||
==Reference== | |||
Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach., Tischkowitz M, Hamel N, Carvalho MA, Birrane G, Soni A, van Beers EH, Joosse SA, Wong N, Novak D, Quenneville LA, Grist SA, Nederlof PM, Goldgar DE, Tavtigian SV, Monteiro AN, Ladias JA, Foulkes WD, Eur J Hum Genet. 2008 Feb 20;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18285836 18285836] | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| Line 25: | Line 31: | ||
[[Category: zinc-finger]] | [[Category: zinc-finger]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Feb 27 07:48:34 2008'' | ||
Revision as of 08:48, 27 February 2008
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X-ray Structure of the BRCA1 BRCT mutant M1775K
OverviewOverview
A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.European Journal of Human Genetics advance online publication, 20 February 2008; doi:10.1038/ejhg.2008.13.
DiseaseDisease
Known diseases associated with this structure: Breast cancer-1 OMIM:[113705], Breast-ovarian cancer OMIM:[113705], Ovarian cancer OMIM:[113705], Papillary serous carcinoma of the peritoneum OMIM:[113705]
About this StructureAbout this Structure
2ING is a Single protein structure of sequence from Homo sapiens with and as ligands. Known structural/functional Sites: , and . Full crystallographic information is available from OCA.
ReferenceReference
Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach., Tischkowitz M, Hamel N, Carvalho MA, Birrane G, Soni A, van Beers EH, Joosse SA, Wong N, Novak D, Quenneville LA, Grist SA, Nederlof PM, Goldgar DE, Tavtigian SV, Monteiro AN, Ladias JA, Foulkes WD, Eur J Hum Genet. 2008 Feb 20;. PMID:18285836
Page seeded by OCA on Wed Feb 27 07:48:34 2008