9o65 | pdb_00009o65

Cryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex

Structural highlights

9o65 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Ligands:	GNP, MG, MN
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 Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway (PubMed:10783161, PubMed:16630891, PubMed:25137548, PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). Acts as a scaffolding protein in the SMP complex (PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). The SMP complex specifically dephosphorylates the inhibitory phosphorylation at 'Ser-259' of RAF1 kinase, 'Ser-365' of BRAF kinase and 'Ser-214' of ARAF kinase, stimulating their kinase activities (PubMed:10783161, PubMed:16630891, PubMed:35768504, PubMed:35830882, PubMed:35831509, PubMed:36175670). The SMP complex enhances the dephosphorylation activity and substrate specificity of PP1c (PubMed:35768504, PubMed:36175670).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

RAF activation is essential for MAPK signaling and is mediated by RAS binding and the dephosphorylation of a conserved phosphoserine by the SHOC2-RAS-PP1C complex. MRAS forms a high-affinity SHOC2-MRAS-PP1C (SMP) complex, while canonical RAS isoforms (KRAS, HRAS, NRAS) form analogous but lower-affinity assemblies. Yet, cancers driven by oncogenic KRAS, HRAS, or NRAS remain strongly SHOC2-dependent, suggesting that these weaker complexes contribute to tumorigenesis. To elucidate how canonical RAS proteins form lower-affinity ternary complexes, the cryo-EM structure of the SHOC2-KRAS-PP1C (SKP) complex stabilized by Noonan syndrome mutations is described. The SKP architecture is similar to the SMP complex but forms fewer contacts and buries less surface area due to the absence of MRAS-specific structural features in KRAS that enhance complex stability. RAS inhibitors MRTX1133 and RMC-6236 alter Switch-I/II conformations, thereby blocking SKP assembly more effectively than they disrupt preformed complexes. These RAS inhibitors do not affect SMP formation because they do not bind MRAS. Since MRAS is upregulated in resistance to KRAS inhibition, we characterize a MRAS mutant capable of binding MRTX1133. This MRAS mutant can form an SMP complex, but MRTX1133 blocks its assembly, demonstrating the feasibility of dual SKP and SMP targeting. Overall, our findings define isoform-specific differences in SHOC2-RAS-PP1C complex formation and support a strategy to prevent both SKP and SMP assemblies to overcome resistance in RAS-driven cancers.

Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.,Bonsor DA, Finci LI, Potter JR, Young LC, Wall VE, Goldstein de Salazar R, Geis KR, Stephens T, Finney J, Nissley DV, McCormick F, Simanshu DK Nat Commun. 2026 Jan 10. doi: 10.1038/s41467-026-68319-1. PMID:41519889^[8]

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:https://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:https://dx.doi.org/10.1002/humu.22634
↑ Liau NPD, Johnson MC, Izadi S, Gerosa L, Hammel M, Bruning JM, Wendorff TJ, Phung W, Hymowitz SG, Sudhamsu J. Structural basis for SHOC2 modulation of RAS signalling. Nature. 2022 Jun 29. pii: 10.1038/s41586-022-04838-3. doi:, 10.1038/s41586-022-04838-3. PMID:35768504 doi:https://dx.doi.org/10.1038/s41586-022-04838-3
↑ Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, Katz S, Park E, Jang DM, Porter KA, Meili F, Guo H, Kerr G, Molle S, Velez-Vega C, Beyer KS, Galli GG, Maira SM, Stams T, Clark K, Eck MJ, Tordella L, Thoma CR, King DA. Structure of the MRAS-SHOC2-PP1C phosphatase complex. Nature. 2022 Jul 13. pii: 10.1038/s41586-022-05086-1. doi:, 10.1038/s41586-022-05086-1. PMID:35830882 doi:https://dx.doi.org/10.1038/s41586-022-05086-1
↑ 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:https://dx.doi.org/10.1038/s41586-022-04928-2
↑ Bonsor DA, Alexander P, Snead K, Hartig N, Drew M, Messing S, Finci LI, Nissley DV, McCormick F, Esposito D, Rodriguez-Viciana P, Stephen AG, Simanshu DK. Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome. Nat Struct Mol Biol. 2022 Oct;29(10):966-977. PMID:36175670 doi:10.1038/s41594-022-00841-4
↑ Bonsor DA, Finci LI, Potter JR, Young LC, Wall VE, Goldstein de Salazar R, Geis KR, Stephens T, Finney J, Nissley DV, McCormick F, Simanshu DK. Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors. Nat Commun. 2026 Jan 10;17(1):1614. PMID:41519889 doi:10.1038/s41467-026-68319-1

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OCA

[1] 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

[2] 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:https://dx.doi.org/10.1016/j.molcel.2006.03.027

[3] 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:https://dx.doi.org/10.1002/humu.22634

[4] Liau NPD, Johnson MC, Izadi S, Gerosa L, Hammel M, Bruning JM, Wendorff TJ, Phung W, Hymowitz SG, Sudhamsu J. Structural basis for SHOC2 modulation of RAS signalling. Nature. 2022 Jun 29. pii: 10.1038/s41586-022-04838-3. doi:, 10.1038/s41586-022-04838-3. PMID:35768504 doi:https://dx.doi.org/10.1038/s41586-022-04838-3

[5] Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, Katz S, Park E, Jang DM, Porter KA, Meili F, Guo H, Kerr G, Molle S, Velez-Vega C, Beyer KS, Galli GG, Maira SM, Stams T, Clark K, Eck MJ, Tordella L, Thoma CR, King DA. Structure of the MRAS-SHOC2-PP1C phosphatase complex. Nature. 2022 Jul 13. pii: 10.1038/s41586-022-05086-1. doi:, 10.1038/s41586-022-05086-1. PMID:35830882 doi:https://dx.doi.org/10.1038/s41586-022-05086-1

[6] 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:https://dx.doi.org/10.1038/s41586-022-04928-2

[7] Bonsor DA, Alexander P, Snead K, Hartig N, Drew M, Messing S, Finci LI, Nissley DV, McCormick F, Esposito D, Rodriguez-Viciana P, Stephen AG, Simanshu DK. Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome. Nat Struct Mol Biol. 2022 Oct;29(10):966-977. PMID:36175670 doi:10.1038/s41594-022-00841-4

[8] Bonsor DA, Finci LI, Potter JR, Young LC, Wall VE, Goldstein de Salazar R, Geis KR, Stephens T, Finney J, Nissley DV, McCormick F, Simanshu DK. Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors. Nat Commun. 2026 Jan 10;17(1):1614. PMID:41519889 doi:10.1038/s41467-026-68319-1

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9o65 | pdb_00009o65

Cryo-EM structure of SHOC2-KRAS-PP1CA (SKP) complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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