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Crystal structure of the Smad3-Smad5 MH1 domain chimera bound to the GGCGC site
Structural highlights
DiseaseSMAD3_HUMAN Defects in SMAD3 may be a cause of colorectal cancer (CRC) [MIM:114500. Defects in SMAD3 are the cause of Loeys-Dietz syndrome 3 (LDS3) [MIM:613795. An aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Patients with LDS3 also manifest early-onset osteoarthritis. They lack craniosynostosis and mental retardation. Note=SMAD3 mutations have been reported to be also associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed:21778426). This phenotype is distinguised from LDS3 by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit aneurysms of other arteries, including abdominal aorta, iliac, and/or intracranial arteries (PubMed:21778426), they have been classified as LDS3 by the OMIM resource.[1] [2] FunctionSMAD3_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 SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures (By similarity). Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Publication Abstract from PubMedSmad transcription factors are the main downstream effectors of the Transforming growth factor beta superfamily (TGFbeta) signalling network. The DNA complexes determined here by X-ray crystallography for the Bone Morphogenetic Proteins (BMP) activated Smad5 and Smad8 proteins reveal that all MH1 domains bind [GGC(GC)|(CG)] motifs similarly, although TGFbeta-activated Smad2/3 and Smad4 MH1 domains bind as monomers whereas Smad1/5/8 form helix-swapped dimers. Dimers and monomers are also present in solution, as revealed by NMR. To decipher the characteristics that defined these dimers, we designed chimeric MH1 domains and characterized them using X-ray crystallography. We found that swapping the loop1 between TGFbeta- and BMP- activated MH1 domains switches the dimer/monomer propensities. When we scanned the distribution of Smad-bound motifs in ChIP-Seq peaks (Chromatin immunoprecipitation followed by high-throughput sequencing) in Smad-responsive genes, we observed specific site clustering and spacing depending on whether the peaks correspond to BMP- or TGFbeta-responsive genes. We also identified significant correlations between site distribution and monomer or dimer propensities. We propose that the MH1 monomer or dimer propensity of Smads contributes to the distinct motif selection genome-wide and together with the MH2 domain association, help define the composition of R-Smad/Smad4 trimeric complexes. Unveiling the dimer/monomer propensities of Smad MH1-DNA complexes.,Ruiz L, Kaczmarska Z, Gomes T, Aragon E, Torner C, Freier R, Baginski B, Martin-Malpartida P, de Martin Garrido N, Marquez JA, Cordeiro TN, Pluta R, Macias MJ Comput Struct Biotechnol J. 2021 Jan 6;19:632-646. doi: , 10.1016/j.csbj.2020.12.044. eCollection 2021. PMID:33510867[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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