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/20'>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>.
   
   
==Pathogenic mutations==
==Pathogenic mutations==
*<scene name='75/751104/Cv/21'>Pathogenic mutations in RING domain</scene>.
*<scene name='75/751104/Cv/21'>Pathogenic mutations in RING domain</scene>.


To begin with scenes, please click the green link with the name of the mutation.
*<scene name='75/751104/L22s/7'>Mutation L22S: </scene>
*<scene name='75/751104/L22s/3'>Mutation L22S: </scene> <jmol><jmolLink><script>animation off; frame 1</script><text>Wild type</text></jmolLink></jmol> and the <jmol><jmolLink><script>animation off; frame 2</script><text>Mutation</text></jmolLink></jmol>. <jmol><jmolLink><script>animation off; frame all</script><text>Mutated and wildtype residues together</text></jmolLink></jmol>. Click here to see an <jmol><jmolLink><script>animation on; animation mode loop; frame play</script><text>animation</text></jmolLink></jmol> of both states. Putative new hydrogen bonds were added. <scene name='75/751104/L22s/6'>TextToBeDisplayed</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 </text> 
</jmolLink>
</jmol>
conformation and
<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;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]22;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states. Putative new hydrogen bonds were added.
*<scene name='75/751104/T37k/4'>Mutation T37K:</scene>
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [THR]37;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 [LYS]37;color selectionHalos red;selectionHalos on;
  </script>
  <text>mutation.
  </text>
</jmolLink>
</jmol>
Click here to see the  
<jmol>
<jmolLink>
  <script>
    animation off; frame all; select [LYS]37;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 [LYS]37;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states. 
*<scene name='75/751104/C39r/2'>Mutation C39R:</scene>
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [CYS]39;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]39;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]39;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]39;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states. This mutation causes missing of S-Zn bond.
*<scene name='75/751104/H41r/6'>Mutation H41R:</scene>  
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [HIS]41;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]41;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]41;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]41;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states. This mutation causes missing of N-Zn bond.
*<scene name='75/751104/C44s/4'>Mutation C44S:</scene>
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [CYS]44;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]44;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]44;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]44;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states. This mutation causes missing of S-Zn bond.
*<scene name='75/751104/C44y/4'>Mutation C44Y:</scene>  
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [CYS]44;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]44;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]44;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]44;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states. This mutation causes missing of S-Zn bond.


'''MY EXAMPLE:'''
=== Very severe pathogenic mutation ===
*<scene name='75/751104/L22s/5'>Mutation L22S: </scene> <jmol><jmolLink><script>animation off; frame 2</script><text>Mutation</text></jmolLink></jmol> and the <jmol><jmolLink><script>animation off; frame 1</script><text>Wild type</text></jmolLink></jmol>. <jmol><jmolLink><script>animation off; frame all</script><text>Mutated and wildtype residues together</text></jmolLink></jmol>. Click here to see an <jmol><jmolLink><script>animation on; animation mode loop; frame play</script><text>animation</text></jmolLink></jmol> of both states. <jmol><jmolButton><script>if (_animating); anim pause;set echo bottom left; color echo white; font echo 20 sansserif;echo Animation Paused; else; anim resume; set echo off;endif;</script> <text>Toggle Animation</text></jmolButton></jmol> N.b. putative new hydrogen bonds were added.
*<scene name='75/751104/C61g/4'>Mutation C61G:</scene>  
 
<jmol>
To begin with scenes, please click in the following order: on "Wild type", after that "Mutation" and so on.
<jmolLink>
*'''Mutation L22S:''' <scene name='75/751104/L22s/3'>Wild type</scene> and the <jmol><jmolButton><script>frame next</script><text>Mutation</text></jmolButton></jmol>. <scene name='75/751104/L22s/1'>Mutated and wildtype residues together</scene>. <scene name='75/751104/L22s/2'>Click here to see animation of this scene</scene>. Putative new hydrogen bonds were added.
  <script>
*'''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>. 
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [CYS]61;color selectionHalos green;selectionHalos on;
*'''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.
  </script>
*'''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.
<text>Wild type </text>
*'''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.
</jmolLink>
*'''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.
</jmol>
*'''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.
conformation and
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 2 2 play; animation off; frame 2; select [GLY]61;color selectionHalos red;selectionHalos on;
  </script>
  <text>mutation.
  </text>
</jmolLink>
</jmol>
Click here to see the
<jmol>
<jmolLink>
  <script>
    animation off; frame all; select [GLY]61;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 [GLY]61;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states. This mutation causes missing of S-Zn bond.


==Benign mutations==
==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>.
*<scene name='75/751104/Cv/29'>Mutation K45Q:</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>.  
<jmol>
<jmolLink>
  <script>
    animation on; animation mode loop; frame 1 1 play; animation off; frame 1; select [LYS]45;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]45;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]45;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]45;color selectionHalos red;selectionHalos on;
  </script>
  <text>animation
  </text>
</jmolLink>
</jmol> between the two states.  
*<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 ==

Latest revision as of 12:04, 23 January 2019


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.[1]

. Pathogenic mutations are shown in magenta, benign mutations are shown in green.

Pathogenic mutations

  • .

conformation and Click here to see the residues together, and an between the two states. Putative new hydrogen bonds were added.

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 missing of S-Zn bond.

conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of N-Zn bond.

conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of S-Zn bond.

conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of S-Zn bond.

Very severe pathogenic mutation

conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of S-Zn bond.

Benign mutations

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.

Human BRCA1 ring domain complex with BARD1 ring domain and Zn+2 ions (PDB code 1jm7)

Drag the structure with the mouse to rotate

References

  1. ↑ Brzovic PS, Rajagopal P, Hoyt DW, King MC, Klevit RE. Structure of a BRCA1-BARD1 heterodimeric RING-RING complex. Nat Struct Biol. 2001 Oct;8(10):833-7. PMID:11573085 doi:10.1038/nsb1001-833

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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