Clark Serena L, Rodriguez Ana M, Snyder Russell R, Hankins Gary D V, Boehning Darren
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, 77550.
Comput Struct Biotechnol J. 2012 Apr 1;1(1). doi: 10.5936/csbj.201204005.
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 11-13, 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.
BRCA1是一种多结构域蛋白，在很大比例的遗传性乳腺癌和卵巢癌中发生突变。BRCA1最常发生突变的三个结构域或区域为：N端RING结构域、外显子11 - 13以及BRCT结构域。BRCA1的RING结构域负责BRCA1的E3泛素连接酶活性，并介导BRCA1与其他蛋白质之间的相互作用。BRCA1使多种具有不同功能的蛋白质发生泛素化。BRCA1的BRCT结构域与具有特定序列的磷酸化蛋白结合，这些序列可被BRCA1和ATM/ATR激酶识别。对RING和BRCT结构域的结构研究揭示了致癌突变影响BRCA1功能的分子基础。虽然目前尚无外显子11 - 13编码氨基酸的结构数据，但该区域存在多个结合位点和功能域。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。在本综述中，我们研究了BRCA1蛋白的结构 - 功能关系及其与癌症进展的相关性。
