Journal
NUCLEIC ACIDS RESEARCH
Volume 46, Issue 22, Pages 12139-12153Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky925
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Funding
- Platform for Drug Discovery, Informatics and Structural Life Science (PDIS) from the Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Society for the Promotion of Science (JSPS) KAKENHI [15K14708, 17K19581, 23228003]
- JSPS KAKENHI [17K19581]
- 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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