Abstract
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.
Highlights
BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers
This study reported that BRCA1/BARD1 heterodimerization of the RING finger with respect to the flanking alpha-helices
The was not affected by Site II mutations, a later study by the interaction between BRCA1 and BARD1 both increases the ubiquitin same group reported that several Site I and Site II mutations caused ligase activity of BRCA1 and causes the nuclear export sequence a decrease in ubiquitin ligase activity, and a decrease in (NES), located on the C-terminal helix of the RING domain of both co-immunoprecipitation of BRCA1 and BARD1 [29]
Summary
The RING (Really Interesting New Gene) domain of BRCA1 consists of a RING finger and two flanking alpha helices encompassing amino acids 1-109 (exons 2-7) [13, 23]. The was not affected by Site II mutations, a later study by the interaction between BRCA1 and BARD1 both increases the ubiquitin same group reported that several Site I and Site II mutations caused ligase activity of BRCA1 and causes the nuclear export sequence a decrease in ubiquitin ligase activity, and a decrease in (NES), located on the C-terminal helix of the RING domain of both co-immunoprecipitation of BRCA1 and BARD1 [29]. A putative coiled-coil domain spanning exons 11-13 in BRCA1 (a.a. 1364-1437) contains the binding site for PALB2 At this site, PALB2 acts as a scaffold to bring together BRCA1 and BRCA2 to form a complex of the three proteins which is involved in HR during DNA repair. PALB2 acts as a scaffold to bring together BRCA1 and BRCA2 to form a complex of the three proteins which is involved in HR during DNA repair Both BRCA1 and PALB2 contain coiled-coil domains that mediate the interaction of the two proteins.
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