Mutation:BRCA1: Difference between revisions

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Sequence

⎈ mutations with manual annotation; pathogenic; benign; not yet reviewed;
wild type Show which residues have mutations:
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<StructureSection load='' size='340' side='right' caption='' scene=''>
<StructureSection load='' size='340' side='right' caption='' scene=''>
Germline mutations in the BRCA1 tumor suppressor gene often result in a significant increase in susceptibility to breast and ovarian cancers. Although the molecular basis of their effects remains largely obscure, many mutations are known to target the highly conserved C-terminal BRCT repeats that function as a phosphoserine/phosphothreonine-binding module. <ref>PMID: 15133502</ref>
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The most common cause of monogenic disease is a single base DNA variant resulting in an amino acid substitution. A set of structural effects, such as reduction in hydrophobic area, overpacking, backbone strain, and loss of electrostatic interactions, is used to represent the impact of single residue mutations on protein stability. The distinction between disease and non-disease variants, strongly supports the hypothesis that loss of protein stability is a major factor contributing to monogenic disease.<ref>pmid 16169011</ref>
A number of germline mutations in BRCA1 are known to substantially increase a carrier’s risk of breast and ovarian cancer. Human BRCA1 is a large protein and appears to be mostly disordered except for the N terminal RING domain and tandem BRCT domains at the C terminus. Many cancer risk mutations truncate the protein, consistent with low or absent in vivo protein levels. There are also a number of missense mutations in the structured regions. Most of these are too rare for clinical significance to have been established, and inspection of the structural context as well as analysis of sequence conservation may help distinguish those which are pathogenic from the benign ones.
<ref>PMID: 15133502</ref>


* '''ToDo''': cleanup elements between mutations display
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.  
* '''ToDo''': use ConSurf colouring on structure.
* '''ToDo''': Implement Template to render ALL mutations of a given model with ConSurf colouring.
* '''ToDo''': Check if model(s) structure loaded before displaying a mutation, to enable showing other structures and back to the sequence/model interaction. Currently model(s) structure loaded only on initial page loading.


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== Authorship ==
See all Pathogenic and benign mutations for [[Mutations_in_BRCA1/BARD1_RING-domain_heterodimer|BRCA1/BARD1_RING domain]] and [[Mutations_in_Brca1_BRCT_Domains|BRCA1/BRCT domain]]
Data on these pages are compiled by [[User:Yizhou_Yin|Yizhou Yin]], [[User:Lipika_Ray|Lipika Ray Pal]] and [[User:John_Moult|John Moult]] (IBBR, University of Maryland, USA). The mutation interface is built by [[User:Jaime_Prilusky|Jaime Prilusky]] and [[User:Joel_L._Sussman|Joel Sussman]] (Weizmann Institute, Israel) and [[User:Angel_Herraez|Angel Herráez]] (Universidad de Alcalá, Spain). The work is supported by NIH R01 GM120364.
-->
 
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</StructureSection>
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== References ==
== References ==
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[[Category: Mutations]]

Latest revision as of 07:46, 28 June 2019

A number of germline mutations in BRCA1 are known to substantially increase a carrier’s risk of breast and ovarian cancer. Human BRCA1 is a large protein and appears to be mostly disordered except for the N terminal RING domain and tandem BRCT domains at the C terminus. Many cancer risk mutations truncate the protein, consistent with low or absent in vivo protein levels. There are also a number of missense mutations in the structured regions. Most of these are too rare for clinical significance to have been established, and inspection of the structural context as well as analysis of sequence conservation may help distinguish those which are pathogenic from the benign ones. [1]

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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ReferencesReferences

  1. ↑ Clapperton JA, Manke IA, Lowery DM, Ho T, Haire LF, Yaffe MB, Smerdon SJ. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol. 2004 Jun;11(6):512-8. Epub 2004 May 9. PMID:15133502 doi:10.1038/nsmb775
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