Mutations in Brca1 BRCT Domains

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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>.
<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==
==Pathogenic mutations==
-
*<scene name='75/752201/T1685a/1'>Mutation T1685A</scene>
+
*<scene name='75/752201/T1685a/4'>Mutation T1685A:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
Line 46: Line 46:
</jmolLink>
</jmolLink>
</jmol> between the two states. This mutation causes hydrogen bonds lost.
</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>
<jmol>
<jmolLink>
<jmolLink>
Line 84: Line 84:
</jmolLink>
</jmolLink>
</jmol> between the two states. This mutation causes hydrogen bonds lost.
</jmol> between the two states. This mutation causes hydrogen bonds lost.
-
*<scene name='75/752201/R1899w/1'>Mutation R1699W:</scene>
+
 
 +
*<scene name='75/752201/G1706e/4'>Mutation G1706E:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ARG]1699;color selectionHalos green;selectionHalos on;
+
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLY]1706;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 97: Line 98:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [TRP]1699;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLU]1706;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 107: Line 108:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [TRP]1699;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [GLU]1706;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 116: Line 117:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [TRP]1699;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [GLU]1706;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
</text>
</text>
</jmolLink>
</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.
+
</jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bonds.
-
*<scene name='75/752201/G1706e/1'>Mutation G1706E</scene>
+
 +
*<scene name='75/752201/S1715r/4'>Mutation S1715R:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLY]1706;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>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 135: Line 137:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLU]1706;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>
</script>
<text>mutation.
<text>mutation.
Line 145: Line 147:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [GLU]1706;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [ARG]1715;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 154: Line 156:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [GLU]1706;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [ARG]1715;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
</text>
</text>
</jmolLink>
</jmolLink>
-
</jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bonds.
+
</jmol> between the two states. This mutation causes hydrogen bonds lost, overpacking.
-
*<scene name='75/752201/A1708e/1'>Mutation A1708E:</scene>
+
*<scene name='75/752201/G1738r/4'>Mutation G1738R:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [GLY]1738;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 173: Line 175:
<jmolLink>
<jmolLink>
<script>
<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]1738;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 183: Line 185:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [GLU]1708;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [ARG]1738;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 192: Line 194:
<jmolLink>
<jmolLink>
<script>
<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]1738;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
</text>
</text>
</jmolLink>
</jmolLink>
-
</jmol> between the two states. This mutation causes overpacking, and forms new hydrogen bond.
+
</jmol> between the two states. This mutation causes overpacking.
-
*<scene name='75/752201/S1715r/1'>Mutation S1715R:</scene>
+
*<scene name='75/752201/L1764p/5'>Mutation L1764P:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [LEU]1764;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 211: Line 213:
<jmolLink>
<jmolLink>
<script>
<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 [PRO]1764;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 221: Line 223:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [ARG]1715;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [PRO]1764;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 230: Line 232:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [ARG]1715;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [PRO]1764;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
</text>
</text>
</jmolLink>
</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/I1766s/2'>Mutation I1766S:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [ILE]1766;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 249: Line 251:
<jmolLink>
<jmolLink>
<script>
<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 [SER]1766;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 259: Line 261:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [ARG]1738;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [SER]1766;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 268: Line 270:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [ARG]1738;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 probably decreased hydrophobic interaction.
 +
 
 +
*<scene name='75/752201/C1787s/2'>Mutation C1787S:</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;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [SER]1787;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [SER]1787;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
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.
 +
*<scene name='75/752201/G1788v/4'>Mutation G1788V:</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;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [VAL]1788;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [VAL]1788;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [VAL]1788;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
Line 274: Line 353:
</jmolLink>
</jmolLink>
</jmol> between the two states. This mutation causes overpacking.
</jmol> between the two states. This mutation causes overpacking.
-
*<scene name='75/752201/L1764p/1'>Mutation L1764P:</scene>
+
*<scene name='75/752201/V1838e/1'>Mutation V1838E:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [VAL]1838;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 287: Line 366:
<jmolLink>
<jmolLink>
<script>
<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 [GLU]1838;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 297: Line 376:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [PRO]1764;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [GLU]1838;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 306: Line 385:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [PRO]1764;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [GLU]1838;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
Line 312: Line 391:
</jmolLink>
</jmolLink>
</jmol> between the two states. This mutation causes overpacking.
</jmol> between the two states. This mutation causes overpacking.
-
*<scene name='75/752201/I1766s/1'>Mutation I1766S:</scene>
+
 
 +
=== Very severe pathogenic mutations ===
 +
*<scene name='75/752201/R1899w/4'>Mutation R1699W:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [ARG]1699;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 325: Line 406:
<jmolLink>
<jmolLink>
<script>
<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 [TRP]1699;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 335: Line 416:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [SER]1766;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [TRP]1699;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 344: Line 425:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [SER]1766;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [TRP]1699;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
</text>
</text>
</jmolLink>
</jmolLink>
-
</jmol> between the two states. This mutation probably decreased hydrophobic interaction.
+
</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/M1775r/9'>Mutation M1775R:</scene>
+
*<scene name='75/752201/A1708e/4'>Mutation A1708E:</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;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLU]1708;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [GLU]1708;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
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. This mutation causes overpacking, and forms new hydrogen bond.
 +
*<scene name='75/752201/M1775r/10'>Mutation M1775R:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
Line 356: Line 475:
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 [MET]1775;color selectionHalos green;selectionHalos on;
</script>
</script>
-
<text>Wild type ([[1t15]])</text>
+
<text>Wild type</text>
</jmolLink>
</jmolLink>
</jmol>
</jmol>
Line 365: Line 484:
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 [ARG]1775;color selectionHalos red;selectionHalos on;
</script>
</script>
-
<text>mutation ([[1n5o]]).
+
<text>mutation.
</text>
</text>
</jmolLink>
</jmolLink>
Line 387: Line 506:
</text>
</text>
</jmolLink>
</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>
<jmol>
<jmolLink>
<jmolLink>
Line 426: Line 544:
</text>
</text>
</jmolLink>
</jmolLink>
-
</jmol> between the two states.
+
</jmol> between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase.
-
*<scene name='75/752201/C1787s/1'>Mutation C1787S:</scene>
+
 
 +
==Benign mutations==
 +
*<scene name='75/752201/M1652t/1'>Mutation M1652T:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [MET]1652;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 440: Line 560:
<jmolLink>
<jmolLink>
<script>
<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 [THR]1652;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 450: Line 570:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [SER]1787;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [THR]1652;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 459: Line 579:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [SER]1787;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [THR]1652;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>animation
 +
</text>
 +
</jmolLink>
 +
</jmol> between the two states. This mutation forms the new hydrogen bond.
 +
*<scene name='75/752201/M1652i/1'>Mutation M1652I:</scene>
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [MET]1652;color selectionHalos green;selectionHalos on;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ILE]1652;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [ILE]1652;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [ILE]1652;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
Line 465: Line 623:
</jmolLink>
</jmolLink>
</jmol> between the two states.
</jmol> between the two states.
-
*<scene name='75/752201/G1788v/3'>Mutation G1788V:</scene>
+
*<scene name='75/752201/F1662/1'>Mutation F1662S:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [PHE]1662;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 478: Line 636:
<jmolLink>
<jmolLink>
<script>
<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 [SER]1662;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 488: Line 646:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [VAL]1788;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [SER]1662;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 497: Line 655:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [VAL]1788;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [SER]1662;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
</text>
</text>
</jmolLink>
</jmolLink>
-
</jmol> between the two states. This mutation causes overpacking.
+
</jmol> between the two states. This mutation decreased hydrophobic interaction and forms new hydrogen bonds.
-
*<scene name='75/752201/V1838e/1'>Mutation V1838E:</scene>
+
*<scene name='75/752201/L1664p/1'>Mutation L1664P:</scene>
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<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 [LEU]1664;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 516: Line 674:
<jmolLink>
<jmolLink>
<script>
<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 [PRO]1664;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 526: Line 684:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [GLU]1838;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [PRO]1664;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 535: Line 693:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [GLU]1838;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [PRO]1664;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
Line 541: Line 699:
</jmolLink>
</jmolLink>
</jmol> between the two states. This mutation causes overpacking.
</jmol> between the two states. This mutation causes overpacking.
-
 
+
*<scene name='75/752201/E1682k/1'>Mutation E1682K:</scene>
-
==Benign mutations==
+
-
*<scene name='75/752201/M1652t/1'>Mutation M1652T:</scene>
+
<jmol>
<jmol>
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [MET]1652;color selectionHalos green;selectionHalos on;
+
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLU]1682;color selectionHalos green;selectionHalos on;
</script>
</script>
<text>Wild type </text>
<text>Wild type </text>
Line 556: Line 712:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [THR]1652;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [LYS]1682;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutation.
<text>mutation.
Line 566: Line 722:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation off; frame all; select [THR]1652;color selectionHalos red;selectionHalos on;
+
animation off; frame all; select [LYS]1682;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>mutated and wild type
<text>mutated and wild type
Line 575: Line 731:
<jmolLink>
<jmolLink>
<script>
<script>
-
animation on; animation mode loop; frame play; select [THR]1652;color selectionHalos red;selectionHalos on;
+
animation on; animation mode loop; frame play; select [LYS]1682;color selectionHalos red;selectionHalos on;
</script>
</script>
<text>animation
<text>animation
</text>
</text>
</jmolLink>
</jmolLink>
-
</jmol> between the two states. This mutation forms the new hydrogen bond.
+
</jmol> 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.
 +
*<scene name='75/752201/G1706a/1'>Mutation G1706A:</scene>
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [GLY]1706;color selectionHalos green;selectionHalos on;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ALA]1706;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [ALA]1706;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [ALA]1706;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>animation
 +
</text>
 +
</jmolLink>
 +
</jmol> between the two states. In contrast to the pathogenic mutation G1706E, this mutation causes only slight overpacking.
 +
*<scene name='75/752201/T1720a/1'>Mutation T1720A:</scene>
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [THR]1720;color selectionHalos green;selectionHalos on;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ALA]1720;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [ALA]1720;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [ALA]1720;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>animation
 +
</text>
 +
</jmolLink>
 +
</jmol> between the two states. This mutation causes hydrogen bond lost.
 +
*<scene name='75/752201/R1751q/1'>Mutation R1751Q:</scene>
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ARG]1751;color selectionHalos green;selectionHalos on;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLN]1751;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [GLN]1751;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [GLN]1751;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>animation
 +
</text>
 +
</jmolLink>
 +
</jmol> between the two states. This mutation causes hydrogen bond lost.
 +
*<scene name='75/752201/V1804d/1'>Mutation V1804D:</scene>
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [VAL]1804;color selectionHalos green;selectionHalos on;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ASP]1804;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [ASP]1804;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [ASP]1804;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>animation
 +
</text>
 +
</jmolLink>
 +
</jmol> between the two states. This mutation forms new hydrogen bonds.
 +
*<scene name='75/752201/I1858l/1'>Mutation I1858L:</scene>
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ILE]1858;color selectionHalos green;selectionHalos on;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [LEU]1858;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [LEU]1858;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [LEU]1858;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>animation
 +
</text>
 +
</jmolLink>
 +
</jmol> between the two states.
 +
*<scene name='75/752201/P1859r/1'>Mutation P1859R:</scene>
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [PRO]1859;color selectionHalos green;selectionHalos on;
 +
</script>
 +
<text>Wild type </text>
 +
</jmolLink>
 +
</jmol>
 +
conformation and
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [ARG]1859;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutation.
 +
</text>
 +
</jmolLink>
 +
</jmol>
 +
Click here to see the
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation off; frame all; select [ARG]1859;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>mutated and wild type
 +
</text>
 +
</jmolLink>
 +
</jmol> residues together, and an
 +
<jmol>
 +
<jmolLink>
 +
<script>
 +
animation on; animation mode loop; frame play; select [ARG]1859;color selectionHalos red;selectionHalos on;
 +
</script>
 +
<text>animation
 +
</text>
 +
</jmolLink>
 +
</jmol> between the two states.
</StructureSection>
</StructureSection>
== References ==
== References ==

Current revision

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

References

  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

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"
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