The TGFβ receptor activation process: An inhibitor- to substrate-binding switch

Morgan Huse; Tom W. Muir; Lan Xu; Ye Guang Chen; John Kuriyan; Joan Massagué

doi:10.1016/S1097-2765(01)00332-X

The TGFβ receptor activation process: An inhibitor- to substrate-binding switch

Morgan Huse, Tom W. Muir, Lan Xu, Ye Guang Chen, John Kuriyan, Joan Massagué

Research output: Contribution to journal › Article › peer-review

340 Scopus citations

Abstract

The type I TGFβ receptor (TβR-I) is activated by phosphorylation of the GS region, a conserved juxtamembrane segment located just N-terminal to the kinase domain. We have studied the molecular mechanism of receptor activation using a homogeneously tetraphosphorylated form of TβR-I, prepared using protein semisynthesis. Phosphorylation of the GS region dramatically enhances the specificity of TβR-I for the critical C-terminal serines of Smad2. In addition, tetraphosphorylated TβR-I is bound specifically by Smad2 in a phosphorylation-dependent manner and is no longer recognized by the inhibitory protein FKBP12. Thus, phosphorylation activates TβR-I by switching the GS region from a binding site for an inhibitor into a binding surface for substrate. Our observations suggest that phosphoserine/phosphothreonine-dependent localization is a key feature of the TβR-I/Smad activation process.

Original language	English (US)
Pages (from-to)	671-682
Number of pages	12
Journal	Molecular Cell
Volume	8
Issue number	3
DOIs	https://doi.org/10.1016/S1097-2765(01)00332-X
State	Published - 2001
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/S1097-2765(01)00332-X

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title = "The TGFβ receptor activation process: An inhibitor- to substrate-binding switch",

abstract = "The type I TGFβ receptor (TβR-I) is activated by phosphorylation of the GS region, a conserved juxtamembrane segment located just N-terminal to the kinase domain. We have studied the molecular mechanism of receptor activation using a homogeneously tetraphosphorylated form of TβR-I, prepared using protein semisynthesis. Phosphorylation of the GS region dramatically enhances the specificity of TβR-I for the critical C-terminal serines of Smad2. In addition, tetraphosphorylated TβR-I is bound specifically by Smad2 in a phosphorylation-dependent manner and is no longer recognized by the inhibitory protein FKBP12. Thus, phosphorylation activates TβR-I by switching the GS region from a binding site for an inhibitor into a binding surface for substrate. Our observations suggest that phosphoserine/phosphothreonine-dependent localization is a key feature of the TβR-I/Smad activation process.",

author = "Morgan Huse and Muir, {Tom W.} and Lan Xu and Chen, {Ye Guang} and John Kuriyan and Joan Massagu{\'e}",

note = "Funding Information: We thank H. Viguet for technical support. Staff members at the Cornell High Energy Synchrotron Source are gratefully acknowledged along with D. Jeruzalmi and M. Young for help with data collection. We are grateful to Y. Shi for helpful advice regarding Smad expression and purification. Additional thanks go to members of the Kuriyan and Muir labs for many helpful suggestions and discussions. M.H. is a National Science Foundation Predoctoral Fellow. L.X. is supported by a Damon Runyon-Walter Winchell Foundation Fellowship. Additional support was supplied by a Pew Scholarship in the Biomedical Sciences to T.W.M. and by National Institutes of Health grants to J.M. (CA34610), T.W.M. (GM5584301), and the Memorial Sloan-Kettering Cancer Center. ",

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AU - Huse, Morgan

AU - Muir, Tom W.

AU - Xu, Lan

AU - Chen, Ye Guang

AU - Kuriyan, John

AU - Massagué, Joan

N1 - Funding Information: We thank H. Viguet for technical support. Staff members at the Cornell High Energy Synchrotron Source are gratefully acknowledged along with D. Jeruzalmi and M. Young for help with data collection. We are grateful to Y. Shi for helpful advice regarding Smad expression and purification. Additional thanks go to members of the Kuriyan and Muir labs for many helpful suggestions and discussions. M.H. is a National Science Foundation Predoctoral Fellow. L.X. is supported by a Damon Runyon-Walter Winchell Foundation Fellowship. Additional support was supplied by a Pew Scholarship in the Biomedical Sciences to T.W.M. and by National Institutes of Health grants to J.M. (CA34610), T.W.M. (GM5584301), and the Memorial Sloan-Kettering Cancer Center.

PY - 2001

Y1 - 2001

N2 - The type I TGFβ receptor (TβR-I) is activated by phosphorylation of the GS region, a conserved juxtamembrane segment located just N-terminal to the kinase domain. We have studied the molecular mechanism of receptor activation using a homogeneously tetraphosphorylated form of TβR-I, prepared using protein semisynthesis. Phosphorylation of the GS region dramatically enhances the specificity of TβR-I for the critical C-terminal serines of Smad2. In addition, tetraphosphorylated TβR-I is bound specifically by Smad2 in a phosphorylation-dependent manner and is no longer recognized by the inhibitory protein FKBP12. Thus, phosphorylation activates TβR-I by switching the GS region from a binding site for an inhibitor into a binding surface for substrate. Our observations suggest that phosphoserine/phosphothreonine-dependent localization is a key feature of the TβR-I/Smad activation process.

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The TGFβ receptor activation process: An inhibitor- to substrate-binding switch

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