5zoj
From Proteopedia
Crystal structure of human SMAD2-MAN1 complex
Structural highlights
Disease[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[SMAD2_HUMAN] Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.[1] [2] [3] [4] [5] [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.[6] [7] 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[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
