Mutations in Brca1 BRCT Domains

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(Difference between revisions)

Revision as of 09:59, 12 February 2017

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. We report the X-ray crystal structure at a resolution of 1.85 A of the BRCA1 tandem BRCT domains in complex with a phosphorylated peptide representing the minimal interacting region of the DEAH-box helicase BACH1. The structure reveals the determinants of this novel class of BRCA1 binding events. We show that a subset of disease-linked mutations act through specific disruption of phospho-dependent BRCA1 interactions rather than through gross structural perturbation of the tandem BRCT domains.^[1]

. Pathogenic mutations are shown in magenta, benign mutations are shown in green, residues with both pathogenic and benign mutations are shown in plum.

Pathogenic mutations

To begin with scenes, please click in the following order: on "Wild type", after that "Mutation" and so on.

Mutation T1685A: and the . . . This mutation causes hydrogen bonds lost.
Mutation T1685I: and the . . . This mutation causes hydrogen bonds lost.
Mutation R1699W: and the . . . This mutation causes saltbridges lost, hydrogen bonds lost, overpacking, clashes; interaction lost with BRCA1 interacting protein C-terminal helicase 1.
Mutation G1706E: and the . . . This mutation causes overpacking, and forms new hydrogen bonds.
Mutation A1708E: and the . . . This mutation causes overpacking, and forms new hydrogen bond.
Mutation S1715R: and the . . . This mutation causes hydrogen bonds lost, overpacking.
Mutation G1738R: and the . . . This mutation causes overpacking.
Mutation L1764P: and the . . . This mutation causes overpacking.
Mutation L1764P: and the . This mutation probably decreased hydrophobic interaction.
Mutation M1775R: (1t15) and (1n5o)^[2]. . .

References

↑ 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
↑ Williams RS, Glover JN. Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J Biol Chem. 2003 Jan 24;278(4):2630-5. Epub 2002 Nov 8. PMID:12427738 doi:10.1074/jbc.M210019200

Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky, Michal Harel, Joel L. Sussman

Retrieved from "http://52.214.119.220/wiki/index.php/Mutations_in_Brca1_BRCT_Domains"

Categories: Disease Molecular Analysis on Proteins | Molecular Pathology | Protein Pathology | Impact of Mutations | Effect of Mutations

@@ Line 17: / Line 17: @@
 *'''Mutation L1764P:''' <scene name='75/752201/L1764p/1'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/752201/L1764p/4'>Mutated and wildtype residues together</scene>. <scene name='75/752201/L1764p/3'>Click here to see animation of this scene</scene>. This mutation causes overpacking.
 *'''Mutation L1764P:''' <scene name='75/752201/I1766s/1'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. This mutation probably decreased hydrophobic interaction.
-*'''Mutation M1775R:''' <scene name='75/752201/M1775r/2'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. This mutation causes overpacking.
+*'''Mutation M1775R:''' <scene name='75/752201/M1775r/4'>Native hydrogen bonding interactions proximal to M1775</scene> ([[1t15]]) and <scene name='75/752201/M1775r/5'>hydrogen bonding, salt bridging for mutant M1775R. Arg-1775 participates in the coordination of two solvent
-*'''Mutation M1775R:''' <scene name='75/752201/M1775k/1'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. This mutation causes overpacking.
+anions, S1 and S2, and has been flipped out from the hydrophobic pocket where Met-1775 normally packs</scene> ([[1n5o]])<ref>PMID: 12427738</ref>. <scene name='75/752201/M1775r/6'>Mutated and wildtype residues together</scene>. <scene name='75/752201/M1775r/7'>Click here to see animation of this scene</scene>.
 </StructureSection>
 == References ==

Mutations in Brca1 BRCT Domains

From Proteopedia

Revision as of 09:59, 12 February 2017

Pathogenic mutations

References

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