Mutations in Brca1 BRCT Domains

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Human BRCA1 (blue) complex with phosphoserine-containing BRCA1 interacting protein C-terminal helicase 1 (olive) (PDB code 1t15)

Drag the structure with the mouse to rotate

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

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking, and forms new hydrogen bonds.

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost, overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation probably decreased hydrophobic interaction.

conformation and Click here to see the residues together, and an between the two states.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

Very severe pathogenic mutations

conformation and Click here to see the residues together, and an between the two states. This mutation causes saltbridges lost, hydrogen bonds lost, overpacking, clashes; interaction lost with BRCA1 interacting protein C-terminal helicase 1.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking, and forms new hydrogen bond.

conformation and Click here to see the residues together, and an between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase.

Benign mutations

conformation and Click here to see the residues together, and an between the two states. This mutation forms the new hydrogen bond.

conformation and Click here to see the residues together, and an between the two states.

conformation and Click here to see the residues together, and an between the two states. This mutation decreased hydrophobic interaction and forms new hydrogen bonds.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation is very interesting. There is rare interaction between 2 GLU resudues in Wild type, it is exchanged by saltbridge in the mutant.

conformation and Click here to see the residues together, and an between the two states. In contrast to the pathogenic mutation G1706E, this mutation causes only slight overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bond lost.

conformation and Click here to see the residues together, and an between the two states. This mutation forms new hydrogen bonds.

conformation and Click here to see the residues together, and an between the two states.

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

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 1: / Line 1: @@
-<StructureSection load='1T15_w_HybridPeptide.pdb' size='450' side='right' caption='' scene='75/752201/Cv/5' pspeed='8'>
+<StructureSection load='1T15_w_HybridPeptide.pdb' size='350' side='right' caption='Human BRCA1 (blue) complex with phosphoserine-containing BRCA1 interacting protein C-terminal helicase 1 (olive) (PDB code [[1t15]])' scene='75/752201/Cv/5' pspeed='8'>
-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.<ref>PMID: 15133502</ref>
+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.<ref>PMID: 15133502</ref>
 <scene name='75/752201/Cv/4'>Brca1 BRCT domains in complex with the phosphorylated interacting region from Bach1 Helicase</scene>.
@@ Line 8: / Line 8: @@
 ==Pathogenic mutations==
-*<scene name='75/752201/T1685a/1'>Mutation T1685A</scene>
+*<scene name='75/752201/T1685a/4'>Mutation T1685A:</scene>
 <jmol>
  <jmolLink>
@@ Line 46: / Line 46: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes hydrogen bonds lost.
-*<scene name='75/752201/T1685i/1'>Mutation T1685I:</scene>
+*<scene name='75/752201/T1685i/5'>Mutation T1685I:</scene>
 <jmol>
  <jmolLink>
@@ Line 85: / Line 85: @@
 </jmol> between the two states. This mutation causes hydrogen bonds lost.
-*<scene name='75/752201/G1706e/1'>Mutation G1706E</scene>
+*<scene name='75/752201/G1706e/4'>Mutation G1706E:</scene>
 <jmol>
  <jmolLink>
@@ Line 124: / Line 124: @@
 </jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bonds.
-*<scene name='75/752201/S1715r/1'>Mutation S1715R:</scene>
+*<scene name='75/752201/S1715r/4'>Mutation S1715R:</scene>
 <jmol>
  <jmolLink>
@@ Line 162: / Line 162: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes hydrogen bonds lost, overpacking.
-*<scene name='75/752201/G1738r/1'>Mutation G1738R:</scene>
+*<scene name='75/752201/G1738r/4'>Mutation G1738R:</scene>
 <jmol>
  <jmolLink>
@@ Line 200: / Line 200: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes overpacking.
-*<scene name='75/752201/L1764p/1'>Mutation L1764P:</scene>
+*<scene name='75/752201/L1764p/5'>Mutation L1764P:</scene>
 <jmol>
  <jmolLink>
@@ Line 238: / Line 238: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes overpacking.
-*<scene name='75/752201/I1766s/1'>Mutation I1766S:</scene>
+*<scene name='75/752201/I1766s/2'>Mutation I1766S:</scene>
 <jmol>
  <jmolLink>
@@ Line 277: / Line 277: @@
 </jmol> between the two states. This mutation probably decreased hydrophobic interaction.
-*<scene name='75/752201/C1787s/1'>Mutation C1787S:</scene>
+*<scene name='75/752201/C1787s/2'>Mutation C1787S:</scene>
 <jmol>
  <jmolLink>
@@ Line 315: / Line 315: @@
  </jmolLink>
 </jmol> between the two states.
-*<scene name='75/752201/G1788v/3'>Mutation G1788V:</scene>
+*<scene name='75/752201/G1788v/4'>Mutation G1788V:</scene>
 <jmol>
  <jmolLink>
@@ Line 393: / Line 393: @@
 === Very severe pathogenic mutations ===
-*<scene name='75/752201/R1899w/1'>Mutation R1699W:</scene>
+*<scene name='75/752201/R1899w/4'>Mutation R1699W:</scene>
 <jmol>
  <jmolLink>
@@ Line 431: / Line 431: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes saltbridges lost, hydrogen bonds lost, overpacking, clashes; '''interaction lost with BRCA1 interacting protein C-terminal helicase 1'''.
-*<scene name='75/752201/A1708e/1'>Mutation A1708E:</scene>
+*<scene name='75/752201/A1708e/4'>Mutation A1708E:</scene>
 <jmol>
  <jmolLink>
@@ Line 469: / Line 469: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bond.
-*<scene name='75/752201/M1775r/9'>Mutation M1775R:</scene>
+*<scene name='75/752201/M1775r/10'>Mutation M1775R:</scene>
 <jmol>
  <jmolLink>
@@ Line 478: / Line 478: @@
  </jmolLink>
 </jmol>
-([[1t15]]) conformation and
+conformation and
 <jmol>
  <jmolLink>
@@ Line 484: / Line 484: @@
     animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ARG]1775;color selectionHalos red;selectionHalos on;
   </script>
-  <text>mutation
+  <text>mutation.
   </text>
  </jmolLink>
 </jmol>
-([[1n5o]]). Click here to see the
+Click here to see the
 <jmol>
  <jmolLink>
@@ Line 506: / Line 506: @@
   </text>
  </jmolLink>
-</jmol> between the two states. Hydrogen bonding, salt bridging for mutant M1775R. Arg1775 participates in the coordination of two solvent
+</jmol> between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase.
-anions, S1 and S2, and has been flipped out from the hydrophobic pocket where Met1775 normally packs <ref>PMID: 12427738</ref>.
+*<scene name='75/752201/M1775k/5'>Mutation M1775K:</scene>
-*<scene name='75/752201/M1775k/3'>Mutation M1775K:</scene>
 <jmol>
  <jmolLink>
@@ Line 545: / Line 544: @@
   </text>
  </jmolLink>
-</jmol> between the two states.
+</jmol> between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase.
 ==Benign mutations==

Mutations in Brca1 BRCT Domains

From Proteopedia

Current revision

Pathogenic mutations

Very severe pathogenic mutations

Benign mutations

References

Proteopedia Page Contributors and Editors (what is this?)

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