4.8 Article

Structural basis for receptor-regulated SMAD recognition by MAN1

期刊

NUCLEIC ACIDS RESEARCH
卷 46, 期 22, 页码 12139-12153

出版社

OXFORD UNIV PRESS
DOI: 10.1093/nar/gky925

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资金

  1. Platform for Drug Discovery, Informatics and Structural Life Science (PDIS) from the Ministry of Education, Culture, Sports, Science and Technology, Japan
  2. Japan Society for the Promotion of Science (JSPS) KAKENHI [15K14708, 17K19581, 23228003]
  3. JSPS KAKENHI [17K19581]
  4. Grants-in-Aid for Scientific Research [17K19581, 15K14708] Funding Source: KAKEN

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Receptor-regulated SMAD (R-SMAD: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8) proteins are key transcription factors of the transforming growth factor-beta (TGF-beta) superfamily of cytokines. MAN1, an integral protein of the inner nuclear membrane, is a SMAD cofactor that terminates TGF-beta superfamily signals. Heterozygous loss-of-function mutations in MAN1 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. MAN1 interacts with MAD homology 2 (MH2) domains of R-SMAD proteins using its C-terminal U2AF homology motif (UHM) domain and UHM ligand motif (ULM) and facilitates R-SMAD dephosphorylation. Here, we report the structural basis for R-SMAD recognition by MAN1. The SMAD2-MAN1 and SMAD1-MAN1 complex structures show that an intramolecular UHM-ULM interaction of MAN1 forms a hydrophobic surface that interacts with a hydrophobic surface among the H2 helix, the strands beta 8 and beta 9, and the L3 loop of the MH2 domains of R-SMAD proteins. The complex structures also show the mechanism by which SMAD cofactors distinguish R-SMAD proteins that possess a highly conserved molecular surface.

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