Mutation:BRCA1: Difference between revisions
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Mutations are assigned pathogenic or benign status according to the BRCA exchange (https://brcaexchange.org/) and Clinvar annotations. Six of the seven BRCA Exchange established pathogenic mutations in the RING domain act by destabilizing its three-dimensional structure. Five (C39R, H41R, C44Y, C44S and C61G) disrupt liganding to a zinc atom. The two zinc atoms are critical to the integrity of the small domain linking the two helices, so that loss of liganding is disruptive. A sixth mutation, T37K, introduces a large, positively charged residue into the interior of the zinc binding domain, causing destabilization both through over-packing and through costly desolvation of the charged epsilon amino group. The seventh mutation, L22S, lies in the interface between the RING domain and the obligatory BARD1 binding partner. That mutation introduces a buried hydroxyl group with no internal hydrogen bonds to compensate for the desolvation cost, and also creates an internal cavity approximately the size of two methyl groups, so weakening the protein-protein interaction. | Mutations are assigned pathogenic or benign status according to the BRCA exchange (https://brcaexchange.org/) and Clinvar annotations. Six of the seven BRCA Exchange established pathogenic mutations in the RING domain act by destabilizing its three-dimensional structure. Five (C39R, H41R, C44Y, C44S and C61G) disrupt liganding to a zinc atom. The two zinc atoms are critical to the integrity of the small domain linking the two helices, so that loss of liganding is disruptive. A sixth mutation, T37K, introduces a large, positively charged residue into the interior of the zinc binding domain, causing destabilization both through over-packing and through costly desolvation of the charged epsilon amino group. The seventh mutation, L22S, lies in the interface between the RING domain and the obligatory BARD1 binding partner. That mutation introduces a buried hydroxyl group with no internal hydrogen bonds to compensate for the desolvation cost, and also creates an internal cavity approximately the size of two methyl groups, so weakening the protein-protein interaction. | ||
== Authorship == | |||
Data on these pages are compiled by Yizhou Yin, Lipika Ray Pal and John Moult (IBBR, University of Maryland, USA). The mutation interface is built by Jaime Prilusky and Joel Sussman (Weizmann Institute, Israel) and Angel Herráez (Universidad de Alcalá, Spain). The work is supported by NIH R01 GM120364. | |||
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