View source for Mutations in BRCA1/BARD1 RING-domain heterodimer

<StructureSection load='1jm71.pdb' size='450' side='right' caption='' 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>

<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>.
 
==Pathogenic mutations==
*<scene name='75/751104/Cv/21'>Pathogenic mutations in RING domain</scene>.


*<scene name='75/751104/L22s/3'>Mutation L22S: </scene> 
<jmol>
 <jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [LEU]22;color selectionHalos green;selectionHalos on;
  </script>
 <text>Wild type conformation,</text>  
 </jmolLink>
</jmol>
and this renders the
<jmol>
 <jmolLink>
  <script>
    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [SER]22;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]22:C;color selectionHalos red;selectionHalos on; select [LEU]22;color selectionHalos green;selectionHalos on;
  </script>
  <text>Mutated and wildtype residues
  </text>
 </jmolLink>
</jmol> together. Click here to 
<jmol>
 <jmolLink>
  <script>
   animation on; animation mode loop; frame play; select [LEU]22;color selectionHalos green;selectionHalos on; select [SER]22;color selectionHalos red;selectionHalos on;
  </script>
  <text>see animation
  </text>
 </jmolLink>
</jmol> of both states. Putative new hydrogen bonds were added.



*'''Mutation T37K:''' <scene name='75/751104/T37k/3'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/T37k/1'>Mutated and wildtype residues together</scene>. <scene name='75/751104/T37k/2'>Click here to see animation of this scene</scene>.  
*'''Mutation C39R:''' <scene name='75/751104/C39r/1'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/Cv/15'>Mutated and wildtype residues together</scene>. <scene name='75/751104/Cv/16'>Click here to see animation of this scene</scene>. This mutation causes missing of S-Zn bond.
*'''Mutation H41R:''' <scene name='75/751104/H41r/5'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/H41r/3'>Mutated and wildtype residues together</scene>. <scene name='75/751104/H41r/4'>Click here to see animation of this scene</scene>. This mutation causes missing of N-Zn bond.
*'''Mutation C44S:''' <scene name='75/751104/C44s/3'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/C44s/1'>Mutated and wildtype residues together</scene>. <scene name='75/751104/C44s/2'>Click here to see animation of this scene</scene>. This mutation causes missing of S-Zn bond.
*'''Mutation C44Y:''' <scene name='75/751104/C44y/3'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/C44y/1'>Mutated and wildtype residues together</scene>. <scene name='75/751104/C44y/2'>Click here to see animation of this scene</scene> This mutation causes missing of S-Zn bond.
*'''Mutation C61G:''' <scene name='75/751104/C61g/3'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/C61g/1'>Mutated and wildtype residues together</scene>. <scene name='75/751104/C61g/2'>Click here to see animation of this scene</scene> This mutation causes missing of S-Zn bond.

==Benign mutations==
*'''Mutation K45Q:''' <scene name='75/751104/Cv/26'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/Cv/24'>Mutated and wildtype residues together</scene>. <scene name='75/751104/Cv/25'>Click here to see animation of this scene</scene>. 
*'''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>. 
</StructureSection>
== References ==
<references/>
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[[Category: Disease Molecular Analysis on Proteins]]
[[Category: Molecular Pathology]]
[[Category: Protein Pathology]]
[[Category: Impact of Mutations]]
[[Category: Effect of Mutations]]