This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

7t7a

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 07:54, 21 September 2022

Crystal Structure of Human SHOC2: A Leucine-Rich Repeat Protein

Structural highlights

7t7a is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[SHOC2_HUMAN] Noonan syndrome-like disorder with loose anagen hair. The disease is caused by variants affecting the gene represented in this entry.

Function

[SHOC2_HUMAN] Regulatory subunit of protein phosphatase 1 (PP1c) that acts as a M-Ras/MRAS effector and participates in MAPK pathway activation. Upon M-Ras/MRAS activation, targets PP1c to specifically dephosphorylate the 'Ser-259' inhibitory site of RAF1 kinase and stimulate RAF1 activity at specialized signaling complexes.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling(1). SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes(2-5). However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .

Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.,Kwon JJ, Hajian B, Bian Y, Young LC, Amor AJ, Fuller JR, Fraley CV, Sykes AM, So J, Pan J, Baker L, Lee SJ, Wheeler DB, Mayhew DL, Persky NS, Yang X, Root DE, Barsotti AM, Stamford AW, Perry CK, Burgin A, McCormick F, Lemke CT, Hahn WC, Aguirre AJ Nature. 2022 Jul 13. pii: 10.1038/s41586-022-04928-2. doi:, 10.1038/s41586-022-04928-2. PMID:35831509^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Li W, Han M, Guan KL. The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Genes Dev. 2000 Apr 15;14(8):895-900. PMID:10783161
↑ Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F. A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Mol Cell. 2006 Apr 21;22(2):217-30. doi: 10.1016/j.molcel.2006.03.027. PMID:16630891 doi:http://dx.doi.org/10.1016/j.molcel.2006.03.027
↑ Hannig V, Jeoung M, Jang ER, Phillips JA 3rd, Galperin E. A Novel SHOC2 Variant in Rasopathy. Hum Mutat. 2014 Nov;35(11):1290-4. doi: 10.1002/humu.22634. Epub 2014 Sep 11. PMID:25137548 doi:http://dx.doi.org/10.1002/humu.22634
↑ Kwon JJ, Hajian B, Bian Y, Young LC, Amor AJ, Fuller JR, Fraley CV, Sykes AM, So J, Pan J, Baker L, Lee SJ, Wheeler DB, Mayhew DL, Persky NS, Yang X, Root DE, Barsotti AM, Stamford AW, Perry CK, Burgin A, McCormick F, Lemke CT, Hahn WC, Aguirre AJ. Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. Nature. 2022 Jul 13. pii: 10.1038/s41586-022-04928-2. doi:, 10.1038/s41586-022-04928-2. PMID:35831509 doi:http://dx.doi.org/10.1038/s41586-022-04928-2

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7t7a"

@@ Line 3: / Line 3: @@
 <StructureSection load='7t7a' size='340' side='right'caption='[[7t7a]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7t7a]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T7A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T7A FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7t7a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T7A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T7A FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7t7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t7a OCA], [https://pdbe.org/7t7a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t7a RCSB], [https://www.ebi.ac.uk/pdbsum/7t7a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t7a ProSAT]</span></td></tr>
 </table>
 == Disease ==
 [[https://www.uniprot.org/uniprot/SHOC2_HUMAN SHOC2_HUMAN]] Noonan syndrome-like disorder with loose anagen hair. The disease is caused by variants affecting the gene represented in this entry.
 == Function ==
 [[https://www.uniprot.org/uniprot/SHOC2_HUMAN SHOC2_HUMAN]] Regulatory subunit of protein phosphatase 1 (PP1c) that acts as a M-Ras/MRAS effector and participates in MAPK pathway activation. Upon M-Ras/MRAS activation, targets PP1c to specifically dephosphorylate the 'Ser-259' inhibitory site of RAF1 kinase and stimulate RAF1 activity at specialized signaling complexes.<ref>PMID:10783161</ref> <ref>PMID:16630891</ref> <ref>PMID:25137548</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Aguirre, J]]
+[[Category: Aguirre J]]
-[[Category: Bian, Y]]
+[[Category: Bian Y]]
-[[Category: Fuller, C]]
+[[Category: Fuller C]]
-[[Category: Hajian, B]]
+[[Category: Hajian B]]
-[[Category: Kwon, J]]
+[[Category: Kwon J]]
-[[Category: Lemke, C]]
+[[Category: Lemke C]]
-[[Category: Leucine-rich]]
-[[Category: Scaffold]]
-[[Category: Structural protein]]

7t7a

From Proteopedia

Revision as of 07:54, 21 September 2022

Crystal Structure of Human SHOC2: A Leucine-Rich Repeat Protein

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox