6zvq
From Proteopedia
Complex between SMAD2 MH2 domain and peptide from Ski corepressor
Structural highlights
FunctionSMAD2_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] Publication Abstract from PubMedShprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-beta signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-beta signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-beta responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-beta-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes. Mutations in SKI in Shprintzen-Goldberg syndrome lead to attenuated TGF-beta responses through SKI stabilization.,Gori I, George R, Purkiss AG, Strohbuecker S, Randall RA, Ogrodowicz R, Carmignac V, Faivre L, Joshi D, Kjaer S, Hill CS Elife. 2021 Jan 8;10:e63545. doi: 10.7554/eLife.63545. PMID:33416497[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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