STRUCTURE-FUNCTION OF THE TUMOR SUPPRESSOR BRCA1
STRUCTURE-FUNCTION OF THE TUMOR SUPPRESSOR BRCA1
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DOI：
10.5936/csbj.201204005
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发表时间：
2012-04-01
影响因子：
6
通讯作者：
Boehning, Darren
中科院分区：
文献类型：
--
作者：
Clark, Serena L.;Rodriguez, Ana M.;Boehning, Darren
BRCA 1是一种多结构域蛋白，在大部分遗传性乳腺癌和卵巢癌中发生突变。BRCA 1最常在三个结构域或区域突变：N-末端RING结构域、外显子II-I3和BRCT结构域。BRCA 1 RING结构域负责BRCA 1的E3泛素连接酶活性，并介导BRCA 1与其他蛋白质之间的相互作用。BRCA 1泛素化几种具有不同功能的蛋白质。BRCA 1 BRCT结构域与具有BRCA 1和ATM/ATR激酶识别的特异性序列的磷蛋白结合。RING和BRCT结构域的结构研究揭示了致癌突变影响BRCA 1功能的分子基础。虽然外显子11-13编码的氨基酸没有结构数据，但在该区域存在多个结合位点和功能结构域。外显子11-13中的许多突变对这些结构域的功能具有有害影响。在这篇小型综述中，我们研究了BRCA 1蛋白的结构-功能关系及其与癌症进展的相关性。
BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers. BRCA1 is most often mutated in three domains or regions: the N-terminal RING domain, exons II-I3, and the BRCT domain. The BRCA1 RING domain is responsible for the E3 ubiquitin ligase activity of BRCA1 and mediates interactions between BRCA1 and other proteins. BRCA1 ubiquitinates several proteins with various functions. The BRCA1 BRCT domain binds to phosphoproteins with specific sequences recognized by both BRCA1 and ATM/ATR kinases. Structural studies of the RING and BRCT domains have revealed the molecular basis by which cancer causing mutations impact the functions of BRCA1. While no structural data is available for the amino acids encoded by exons 11-13, multiple binding sites and functional domains exist in this region. Many mutations in exons 11-13 have deleterious effects on the function of these domains. In this mini-review, we examine the structure-function relationships of the BRCA1 protein and the relevance to cancer progression.