Breast cancer predisposing mutations: protein structural implications
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BRCA1 · BARD1 · site I · site II · Zn · helices · sheet
The breast cancer susceptibility gene BRCA1 codes for a 1863 amino acid protein involved in gene regulation processes following DNA damage. A variety of mutations in BRCA1 predispose for breast and/or ovarian cancer or prostate cancer (Tavtigan et al., 1998). The structural implications of some of these mutations became evident once the structure of an essential part of the protein was elucidated.
Proteins in biochemical conditions which not favour disulfide bonds have to rely in other means to stabilize their structure. The BRCA-protein contains a RING domain which creates a loop structure by binding two zinc atoms by eight amino acids, where the binding sites are interwoven (Venikataram, 2002).
In site I four cysteines are bound to
the zinc atom via their sulfur atoms,
in site II one cysteine is replaced by histidine
binding via a nitrogen atom. Site
II has a somewhat lower affinity for zinc
than site I . In most patients, it was discovered
that cancer-predisposing mutations in this domain of BRCA1
maped to cysteines 61 or 64 at site II, the cysteines
are then replaced by glycine which cannot contribute to zinc
(Brzovic et al., 2001).
In mutant proteins there is an enhanced proteolytic sensitivity, which reflects the resulting local destabilization previously mentioned. The wild type form of BRCA1 is either a homodimer or forms a heterodimer with a structurally similar protein, BARD1. Dimerization of the domains occurs by the interaction of helices adjoining to the RING motifs to form a four-helix bundle (Venkitaraman, 2001). This dimerization however is not disturbed by either a C61G or a C64G mutation. The surface at the bottom of the heterodimer complex (including site II ) however is implicated in protein interaction needed for the ubiquitination pathway following DNA damage: The RING domain of BRCA1 exhibits an ubiquitin ligase activity (which is enhanced by complexing with BARD1). Mutations exchanging either of the zinc complexing cysteines in site II abolish this activity. The RING domain of BRCA1 also interacts with a de-ubiquitinating enzyme the mechanism of which is not yet clear. The ubiquitine-dependent protein turnover of a cell with mutated BRCA1 seems to be heavily disturbed in several ways (Brzovic et al., 2001).
Some single occurences of amino acid substitutions in cancer patients were found in the helices forming the dimerization interface (the original amino acids are shown here together). Until today, no cancer related amino acid substitutions were found in BARD1. It is to note that BARD1also has a RING domain flanked by the helices used for dimerization with BRCA1. The structure of the RING motif resembles exactly that of the counterpart in BRCA1 (Brzovic et al., 2001).
© Copyright 2005, Department of Biology, Davidson College, Davidson,
Send comments, questions, and suggestions to: Daniela V. Alvarez