Sandbox Reserved 1706: Difference between revisions

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====Conformational Change Linkers====
====Conformational Change Linkers====
These three helical linkers (L1, L2, and L3)(<scene name='90/904311/Linker_closed/4'>Linkers in Closed Conformation</scene>
These three helical linkers (L1, L2, and L3) undergo rotations to relocate the GRD and Sec14-PH sites. Linker 1 (L1) consists of a loop connected by two helices from L1173-M1215 and is the main contributor in rotation of the GRD domain. The rotation of L1 to the <scene name='90/904311/Linkers_open/1'>open conformation</scene>  causes N-HEAT ARM [https://en.wikipedia.org/wiki/Alpha_helix α helix] 48 and GRD helix 49 to extend out, aligning to form a hinge point at G1190. The GRD relocation is assisted by Sec14-PH relocation, which is initiated by Linker 3(L3) from Q1835 to G1852. Movement of L3 is further supported by rearrangement of the proline rich section of the C-HEAT ARM. L1 and L3 also move closer to each other in the <scene name='90/904311/Linkers_open/1'>open conformation</scene> initiating rearrangement of the GRD and Sec14-PH domain. Linker 2 (L2) consists of residues G1547-T1565 and begins at helix 63, the final helix of the GRD site, and connects into the short loop of [https://en.wikipedia.org/wiki/Alpha_helix α helix] 65 of the Sec14-PH domain and also assists in shifting the Sec14-PH away from the GRD site. The combination of these three linkers are largely responsible for the conformational shift of the <scene name='90/904311/Linker_closed/1'> closed conformation</scene>
 
Zoom in"
<jmol>
  <jmolButton>
    <script>moveto 1.0 { -93 -976 -198 100.01} 317.4 0.0 0.0 {364.4077734377054 341.9358671885079 392.3046403678749} 146.92471247967674 {0 0 0} 0 0 0 3.0 0.0 0.0 </script> <text>🔎Zoom In(Closed Linkers)</text>
  </jmolButton>
</jmol>
and the <scene name='90/904311/Linkers_open/2'>Linkers in the Open Conformation</scene>
 
Zoom in"
<jmol>
  <jmolButton>
    <script>moveto 1.0 { 258 942 215 149.04} 254.03 0.0 0.0 {363.6198596926281 345.1996488441136 383.09000113650916} 143.7868028412415 {0 0 0} 0 0 0 3.0 0.0 0.0 </script> <text>🔎Zoom In(Open Linkers)</text>
  </jmolButton>
</jmol>) undergo rotations to relocate the GRD and Sec14-PH sites. Linker 1 (L1) consists of a loop connected by two helices from L1173-M1215 and is the main contributor in rotation of the GRD domain. The rotation of L1 to the <scene name='90/904311/Linkers_open/1'>open conformation</scene>  causes N-HEAT ARM [https://en.wikipedia.org/wiki/Alpha_helix α helix] 48 and GRD helix 49 to extend out, aligning to form a hinge point at G1190. The GRD relocation is assisted by Sec14-PH relocation, which is initiated by Linker 3(L3) from Q1835 to G1852. Movement of L3 is further supported by rearrangement of the proline rich section of the C-HEAT ARM. L1 and L3 also move closer to each other in the <scene name='90/904311/Linkers_open/1'>open conformation</scene> initiating rearrangement of the GRD and Sec14-PH domain. Linker 2 (L2) consists of residues G1547-T1565 and begins at helix 63, the final helix of the GRD site, and connects into the short loop of [https://en.wikipedia.org/wiki/Alpha_helix α helix] 65 of the Sec14-PH domain and also assists in shifting the Sec14-PH away from the GRD site. The combination of these three linkers are largely responsible for the conformational shift of the <scene name='90/904311/Linker_closed/1'> closed conformation</scene>
<scene name='90/904312/Linker_closed/2'>(zoomed in)'</scene> and <scene name='90/904311/Linkers_open/1'>open conformation</scene>
<scene name='90/904312/Linker_closed/2'>(zoomed in)'</scene> and <scene name='90/904311/Linkers_open/1'>open conformation</scene>
<scene name='90/904312/Zoomed_lo/1'>(zoomed in)'</scene>.<ref name="Lupton"> DOI:10.1038/s41594-021-00687-2</ref><ref name="Naschberger"> DOI:10.1038/s41586-021-04024-x</ref>
<scene name='90/904312/Zoomed_lo/1'>(zoomed in)'</scene>.<ref name="Lupton"> DOI:10.1038/s41594-021-00687-2</ref><ref name="Naschberger"> DOI:10.1038/s41586-021-04024-x</ref>


==Ras Binding==
==Ras Binding==
Arg1276 is the critical residue within the GRD site for Ras activation.  In the open conformation, the arginine finger binds to the backbone γ-carbon of Y32 in Ras to assist in eventual hydrolysis of GTP (<scene name='90/904311/Arg_1276_open/14'>Arg 1276</scene>
Arg1276 is the critical residue within the GRD site for Ras activation.  In the open conformation, the arginine finger binds to the backbone γ-carbon of Y32 in Ras to assist in eventual hydrolysis of GTP. In the closed conformation, this interaction between Y32 and GTP is blocked by E31. Removal of the inhibition of E31 from Ras by R1276 from Neurofibromin allows for the normal function of neurofibromin in the rapid rate increase of GTP hydrolysis upon Ras binding. Mutations to the arginine finger slow GTPase activating reaction of neurofibromin.<ref name="Bourne"> DOI:10.1038/39470</ref><ref name="Lupton"> DOI:10.1038/s41594-021-00687-2</ref><ref name="Naschberger"> DOI:10.1038/s41586-021-04024-x</ref>  
Zoomed"
<jmol>
  <jmolButton>
    <script>moveto 1.0 { -776 433 -458 146.98} 7209.11 0.0 0.0 {361.5375833333334 402.0207083333333 360.750125} 190.41144084626742 {0 0 0} 0 0 0 3.0 0.0 0.0</script> <text>🔎Zoom In(Open Arg 1276)</text>
  </jmolButton>
</jmol> ). In the closed conformation, this interaction between Y32 and GTP is blocked by E31. Removal of the inhibition of E31 from Ras by R1276 from Neurofibromin allows for the normal function of neurofibromin in the rapid rate increase of GTP hydrolysis upon Ras binding. Mutations to the arginine finger slow GTPase activating reaction of neurofibromin.<ref name="Bourne"> DOI:10.1038/39470</ref><ref name="Lupton"> DOI:10.1038/s41594-021-00687-2</ref><ref name="Naschberger"> DOI:10.1038/s41586-021-04024-x</ref>  
==SPRED 1==
==SPRED 1==
<scene name='90/904311/Spred1_w_grd/2'>SPRED 1</scene> is another peripheral protein that interacts with the GRD domain of Neurofibromin. SPRED 1 recruits Neurofibromin from the cytosol to the plasma membrane to interact with Ras. Binding of SPRED 1 can occur in either the open or closed conformation and causes a structural rearrangement of the GRD domain and GAPex subdomain that has yet to be structuralized.<ref name="Lupton"> DOI:10.1038/s41594-021-00687-2</ref><ref name="Naschberger"> DOI:10.1038/s41586-021-04024-x</ref>
<scene name='90/904311/Spred1_w_grd/2'>SPRED 1</scene> is another peripheral protein that interacts with the GRD domain of Neurofibromin. SPRED 1 recruits Neurofibromin from the cytosol to the plasma membrane to interact with Ras. Binding of SPRED 1 can occur in either the open or closed conformation and causes a structural rearrangement of the GRD domain and GAPex subdomain that has yet to be structuralized.<ref name="Lupton"> DOI:10.1038/s41594-021-00687-2</ref><ref name="Naschberger"> DOI:10.1038/s41586-021-04024-x</ref>
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