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Mutations in BRCA1/BARD1 RING-domain heterodimer: Difference between revisions

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<StructureSection load='1jm71.pdb' size='450' side='right' caption='' scene='75/751104/Cv/2' pspeed='8'>
<StructureSection load='1jm7.pdb' size='450' side='right' caption='Human BRCA1 ring domain complex with BARD1 ring domain and Zn+2 ions (PDB code [[1jm7]])' scene='75/751104/Cv/2' pspeed='8'>


The RING domain of the breast and ovarian cancer tumor suppressor BRCA1 interacts with multiple cognate proteins, including the RING protein BARD1. Proper function of the BRCA1 RING domain is critical, as evidenced by the many cancer-predisposing mutations found within this domain. We present the solution structure of the heterodimer formed between the RING domains of BRCA1 and BARD1. Comparison with the RING homodimer of the V(D)J recombination-activating protein RAG1 reveals the structural diversity of complexes formed by interactions between different RING domains. The BRCA1–BARD1 structure provides a model for its ubiquitin ligase activity, illustrates how the BRCA1 RING domain can be involved in associations with multiple protein partners and provides a framework for understanding cancer-causing mutations at the molecular level.<ref>PMID: 11573085</ref>
The RING domain of the breast and ovarian cancer '''tumor suppressor BRCA1''' interacts with multiple cognate proteins, including the RING protein BARD1. Proper function of the BRCA1 RING domain is critical, as evidenced by the many cancer-predisposing mutations found within this domain. We present the solution structure of the heterodimer formed between the RING domains of BRCA1 and BARD1. Comparison with the RING homodimer of the V(D)J recombination-activating protein RAG1 reveals the structural diversity of complexes formed by interactions between different RING domains. The BRCA1–BARD1 structure provides a model for its ubiquitin ligase activity, illustrates how the BRCA1 RING domain can be involved in associations with multiple protein partners and provides a framework for understanding cancer-causing mutations at the molecular level.<ref>PMID: 11573085</ref>


<scene name='75/751104/Cv/28'>Pathogenic and benign mutations in RING domain</scene>. <font color='magenta'><b>Pathogenic mutations are shown in magenta</b></font>, <font color='lime'><b>benign mutations are shown in green</b></font>.
<scene name='75/751104/Cv/28'>Pathogenic and benign mutations in RING domain</scene>. <font color='magenta'><b>Pathogenic mutations are shown in magenta</b></font>, <font color='lime'><b>benign mutations are shown in green</b></font>.
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*<scene name='75/751104/Cv/21'>Pathogenic mutations in RING domain</scene>.
*<scene name='75/751104/Cv/21'>Pathogenic mutations in RING domain</scene>.


*<scene name='75/751104/L22s/3'>Mutation L22S: </scene>  
*<scene name='75/751104/L22s/7'>Mutation L22S: </scene>  
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
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  </jmolLink>
  </jmolLink>
</jmol> between the two states. Putative new hydrogen bonds were added.
</jmol> between the two states. Putative new hydrogen bonds were added.
*<scene name='75/751104/T37k/3'>Mutation T37K:</scene>  
*<scene name='75/751104/T37k/4'>Mutation T37K:</scene>  
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
Line 84: Line 84:
  </jmolLink>
  </jmolLink>
</jmol> between the two states.   
</jmol> between the two states.   
*<scene name='75/751104/C39r/1'>Mutation C39R:</scene>  
*<scene name='75/751104/C39r/2'>Mutation C39R:</scene>  
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
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  </jmolLink>
  </jmolLink>
</jmol> between the two states. This mutation causes missing of S-Zn bond.
</jmol> between the two states. This mutation causes missing of S-Zn bond.
*<scene name='75/751104/H41r/5'>Mutation H41R:</scene>  
*<scene name='75/751104/H41r/6'>Mutation H41R:</scene>  
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
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  </jmolLink>
  </jmolLink>
</jmol> between the two states. This mutation causes missing of N-Zn bond.
</jmol> between the two states. This mutation causes missing of N-Zn bond.
*<scene name='75/751104/C44s/3'>Mutation C44S:</scene>  
*<scene name='75/751104/C44s/4'>Mutation C44S:</scene>  
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
Line 198: Line 198:
  </jmolLink>
  </jmolLink>
</jmol> between the two states. This mutation causes missing of S-Zn bond.
</jmol> between the two states. This mutation causes missing of S-Zn bond.
*<scene name='75/751104/C44y/3'>Mutation C44Y:</scene>  
*<scene name='75/751104/C44y/4'>Mutation C44Y:</scene>  
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
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  </jmolLink>
  </jmolLink>
</jmol> between the two states. This mutation causes missing of S-Zn bond.
</jmol> between the two states. This mutation causes missing of S-Zn bond.
*<scene name='75/751104/C61g/3'>Mutation C61G:</scene>  
 
=== Very severe pathogenic mutation ===
*<scene name='75/751104/C61g/4'>Mutation C61G:</scene>  
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
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==Benign mutations==
==Benign mutations==
*<scene name='75/751104/Cv/26'>Mutation K45Q:</scene>
*<scene name='75/751104/Cv/29'>Mutation K45Q:</scene>
<jmol>
<jmol>
  <jmolLink>
  <jmolLink>
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  </jmolLink>
  </jmolLink>
</jmol> between the two states.  
</jmol> between the two states.  
*'''Mutation D67Y:''' <scene name='75/751104/Cv/27'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/Cv/11'>Mutated and wildtype residues together</scene>. <scene name='75/751104/Cv/10'>Click here to see animation of this scene</scene>.  
*<scene name='75/751104/Cv/30'>Mutation D67Y:</scene>
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [ASP]67;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 [TYR]67;color selectionHalos red;selectionHalos on;
  </script>
  <text>mutation.
  </text>
</jmolLink>
</jmol>
Click here to see the
<jmol>
<jmolLink>
  <script>
    animation off; frame all; select [TYR]67;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 [TYR]67;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states.
</StructureSection>
</StructureSection>
== References ==
== References ==

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky, Jaime Prilusky, Joel L. Sussman, Michal Harel
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