Mutations in Brca1 BRCT Domains

From Proteopedia

(Difference between revisions)

Revision as of 09:24, 26 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

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 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 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 mutations

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. Hydrogen bonding, salt bridging for mutant M1775R. Arg1775 participates in the coordination of two solvent anions, S1 and S2, and has been flipped out from the hydrophobic pocket where Met1775 normally packs ^[2].

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

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
↑ 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

Mutations in Brca1 BRCT Domains

From Proteopedia

Revision as of 09:24, 26 February 2017

Pathogenic mutations

Very severe mutations

Benign mutations

References

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@@ Line 160: / Line 160: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bonds.
-*<scene name='75/752201/A1708e/1'>Mutation A1708E:</scene>
+*<scene name='75/752201/S1715r/1'>Mutation S1715R:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ALA]1708;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [SER]1715;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 173: / Line 174: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLU]1708;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ARG]1715;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 183: / Line 184: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [GLU]1708;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [ARG]1715;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 192: / Line 193: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [GLU]1708;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [ARG]1715;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bond.
+</jmol> between the two states. This mutation causes hydrogen bonds lost, overpacking.
-*<scene name='75/752201/S1715r/1'>Mutation S1715R:</scene>
+*<scene name='75/752201/G1738r/1'>Mutation G1738R:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [SER]1715;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLY]1738;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 211: / Line 212: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ARG]1715;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ARG]1738;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 221: / Line 222: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [ARG]1715;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [ARG]1738;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 230: / Line 231: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [ARG]1715;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [ARG]1738;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states. This mutation causes hydrogen bonds lost, overpacking.
+</jmol> between the two states. This mutation causes overpacking.
-*<scene name='75/752201/G1738r/1'>Mutation G1738R:</scene>
+*<scene name='75/752201/L1764p/1'>Mutation L1764P:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLY]1738;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [LEU]1764;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 249: / Line 250: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ARG]1738;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [PRO]1764;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 259: / Line 260: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [ARG]1738;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [PRO]1764;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 268: / Line 269: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [ARG]1738;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [PRO]1764;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
@@ Line 274: / Line 275: @@
  </jmolLink>
 </jmol> between the two states. This mutation causes overpacking.
-*<scene name='75/752201/L1764p/1'>Mutation L1764P:</scene>
+*<scene name='75/752201/I1766s/1'>Mutation I1766S:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [LEU]1764;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ILE]1766;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 287: / Line 288: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [PRO]1764;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [SER]1766;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 297: / Line 298: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [PRO]1764;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [SER]1766;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 306: / Line 307: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [PRO]1764;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [SER]1766;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states. This mutation causes overpacking.
+</jmol> between the two states. This mutation probably decreased hydrophobic interaction.
-*<scene name='75/752201/I1766s/1'>Mutation I1766S:</scene>
+*<scene name='75/752201/C1787s/1'>Mutation C1787S:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ILE]1766;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [CYS]1787;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 325: / Line 327: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [SER]1766;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [SER]1787;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 335: / Line 337: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [SER]1766;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [SER]1787;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 344: / Line 346: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [SER]1766;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [SER]1787;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states. This mutation probably decreased hydrophobic interaction.
+</jmol> between the two states.
-*<scene name='75/752201/M1775r/9'>Mutation M1775R:</scene>
+*<scene name='75/752201/G1788v/3'>Mutation G1788V:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [MET]1775;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLY]1788;color selectionHalos green;selectionHalos on;
   </script>
- <text>Wild type ([[1t15]])</text>
+ <text>Wild type </text>
  </jmolLink>
 </jmol>
@@ Line 363: / Line 365: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ARG]1775;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [VAL]1788;color selectionHalos red;selectionHalos on;
   </script>
-  <text>mutation ([[1n5o]]).
+  <text>mutation.
   </text>
  </jmolLink>
@@ Line 373: / Line 375: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [ARG]1775;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [VAL]1788;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 382: / Line 384: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [ARG]1775;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [VAL]1788;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </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 overpacking.
-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/V1838e/1'>Mutation V1838E:</scene>
-*<scene name='75/752201/M1775k/3'>Mutation M1775K:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [MET]1775;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [VAL]1838;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 402: / Line 403: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [LYS]1775;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLU]1838;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 412: / Line 413: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [LYS]1775;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [GLU]1838;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 421: / Line 422: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [LYS]1775;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [GLU]1838;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states.
+</jmol> between the two states. This mutation causes overpacking.
-*<scene name='75/752201/C1787s/1'>Mutation C1787S:</scene>
+=== Very severe mutations ===
+*<scene name='75/752201/A1708e/1'>Mutation A1708E:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [CYS]1787;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ALA]1708;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 440: / Line 443: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [SER]1787;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLU]1708;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 450: / Line 453: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [SER]1787;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [GLU]1708;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 459: / Line 462: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [SER]1787;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [GLU]1708;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states.
+</jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bond.
-*<scene name='75/752201/G1788v/3'>Mutation G1788V:</scene>
+*<scene name='75/752201/M1775r/9'>Mutation M1775R:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLY]1788;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [MET]1775;color selectionHalos green;selectionHalos on;
   </script>
- <text>Wild type </text>
+ <text>Wild type ([[1t15]])</text>
  </jmolLink>
 </jmol>
@@ Line 478: / Line 481: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [VAL]1788;color selectionHalos red;selectionHalos on;
+    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 ([[1n5o]]).
   </text>
  </jmolLink>
@@ Line 488: / Line 491: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [VAL]1788;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [ARG]1775;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 497: / Line 500: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [VAL]1788;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [ARG]1775;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states. This mutation causes overpacking.
+</jmol> between the two states. Hydrogen bonding, salt bridging for mutant M1775R. Arg1775 participates in the coordination of two solvent
-*<scene name='75/752201/V1838e/1'>Mutation V1838E:</scene>
+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/3'>Mutation M1775K:</scene>
 <jmol>
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [VAL]1838;color selectionHalos green;selectionHalos on;
+    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [MET]1775;color selectionHalos green;selectionHalos on;
   </script>
  <text>Wild type </text>
@@ Line 516: / Line 520: @@
  <jmolLink>
   <script>
-    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLU]1838;color selectionHalos red;selectionHalos on;
+    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [LYS]1775;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutation.
@@ Line 526: / Line 530: @@
  <jmolLink>
   <script>
-    animation off; frame all; select [GLU]1838;color selectionHalos red;selectionHalos on;
+    animation off; frame all; select [LYS]1775;color selectionHalos red;selectionHalos on;
   </script>
   <text>mutated and wild type
@@ Line 535: / Line 539: @@
  <jmolLink>
   <script>
-   animation on; animation mode loop; frame play; select [GLU]1838;color selectionHalos red;selectionHalos on;
+   animation on; animation mode loop; frame play; select [LYS]1775;color selectionHalos red;selectionHalos on;
   </script>
   <text>animation
   </text>
  </jmolLink>
-</jmol> between the two states. This mutation causes overpacking.
+</jmol> between the two states.
 ==Benign mutations==