5zok | pdb_00005zok
Crystal structure of human SMAD1-MAN1 complex.
Structural highlights
Disease[SMAD1_HUMAN] Defects in SMAD1 may be a cause of primary pulmonary hypertension (PPH1) [MIM:178600]. A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.[1] [MAN1_HUMAN] Isolated osteopoikilosis;Buschke-Ollendorff syndrome;12q14 microdeletion syndrome;Melorheostosis with osteopoikilosis. The disease is caused by mutations affecting the gene represented in this entry. Function[SMAD1_HUMAN] Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase. SMAD1 is a receptor-regulated SMAD (R-SMAD). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.[2] [MAN1_HUMAN] Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins. Antagonizes TGF-beta-induced cell proliferation arrest.[3] [4] Publication Abstract from PubMedReceptor-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 beta8 and beta9, 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. Structural basis for receptor-regulated SMAD recognition by MAN1.,Miyazono KI, Ohno Y, Wada H, Ito T, Fukatsu Y, Kurisaki A, Asashima M, Tanokura M Nucleic Acids Res. 2018 Oct 13. pii: 5128924. doi: 10.1093/nar/gky925. PMID:30321401[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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