Smad1 Recognition and Activation by the ALK1 Group of Transforming Growth Factor-β Family Receptors*
- From the Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Abstract
Two structural elements, the L45 loop on the kinase domain of the transforming growth factor-β (TGF-β) family type I receptors and the L3 loop on the MH2 domain of Smad proteins, determine the specificity of the interactions between these receptors and Smad proteins. The L45 sequence of the TGF-β type I receptor (TβR-I) specifies Smad2 interaction, whereas the related L45 sequence of the bone morphogenetic protein (BMP) type I receptor (BMPR-I) specifies Smad1 interactions. Here we report that members of a third receptor group, which includes ALK1 and ALK2 from vertebrates and Saxophone from Drosophila, specifically phosphorylate and activate Smad1 even though the L45 sequence of this group is very divergent from that of BMPR-I. We investigated the structural elements that determine the specific recognition of Smad1 by ALK1 and ALK2. In addition to the receptor L45 loop and the Smad1 L3 loop, the specificity of this recognition requires the α-helix 1 of Smad1. The α-helix 1 is a conserved structural element located in the vicinity of the L3 loop on the surface of the Smad MH2 domain. Thus, Smad1 recognizes two distinct groups of receptors, the BMPR-I group and the ALK1 group, through different L45 sequences on the receptor kinase domain and a differential use of two surface structures on the Smad1 MH2 domain.
Footnotes
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↵* This work was supported by National Institutes of Health Grant CA34610 (to J. M.) and a Cancer Center grant to the Memorial Sloan-Kettering Cancer Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Research Associate of the Howard Hughes Medical Institute.
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↵§ Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Box 116, Memorial Sloan-Kettering Cancer Ctr., 1275 York Ave., New York, NY 10021. Tel.: 212-639-8975; Fax: 212-717-3298; E-mail: j-massague{at}ski.mskcc.org.
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↵2 F. Liu and J. Massagué, unpublished work on A3-Luc.
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↵3 M. Kretzschmar, J. Doody, and J. Massagué, unpublished work.
- Abbreviations:
- TGF-β
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transforming growth factor β
- BMP
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bone morphogenetic protein.
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- Received November 5, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
