7zdd
From Proteopedia
Crystal structure of TRIM33 PHD-Bromodomain isoform B in complex with H3K10ac histone peptide.
Structural highlights
DiseaseTRI33_HUMAN Papillary or follicular thyroid carcinoma. The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving TRIM33 is found in thyroid papillary carcinomas. Translocation t(1;10)(p13;q11) with RET. The translocation generates the TRIM33/RET (PTC7) oncogene. FunctionTRI33_HUMAN Acts as an E3 ubiquitin-protein ligase. Promotes SMAD4 ubiquitination, nuclear exclusion and degradation via the ubiquitin proteasome pathway. According to PubMed:16751102, does not promote a decrease in the level of endogenous SMAD4. May act as a transcriptional repressor. Inhibits the transcriptional response to TGF-beta/BMP signaling cascade. Plays a role in the control of cell proliferation. Its association with SMAD2 and SMAD3 stimulates erythroid differentiation of hematopoietic stem/progenitor (By similarity). Monoubiquitinates SMAD4 and acts as an inhibitor of SMAD4-dependent TGF-beta/BMP signaling cascade (Monoubiquitination of SMAD4 hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade).[1] [2] [3] [4] Publication Abstract from PubMedTRIM33 is a member of the tripartite motif (TRIM) family of proteins, some of which possess E3 ligase activity and are involved in the ubiquitin-dependent degradation of proteins. Four of the TRIM family proteins, TRIM24 (TIF1alpha), TRIM28 (TIF1beta), TRIM33 (TIF1gamma) and TRIM66, contain C-terminal plant homeodomain (PHD) and bromodomain (BRD) modules, which bind to methylated lysine (KMen) and acetylated lysine (KAc), respectively. Here we investigate the differences between the two isoforms of TRIM33, TRIM33alpha and TRIM33beta, using structural and biophysical approaches. We show that the N1039 residue, which is equivalent to N140 in BRD4(1) and which is conserved in most BRDs, has a different orientation in each isoform. In TRIM33beta, this residue coordinates KAc, but this is not the case in TRIM33alpha. Despite these differences, both isoforms show similar affinities for H31-27K18Ac, and bind preferentially to H31-27K9Me3K18Ac. We used this information to develop an AlphaScreen assay, with which we have identified four new ligands for the TRIM33 PHD-BRD cassette. These findings provide fundamental new information regarding which histone marks are recognized by both isoforms of TRIM33 and suggest starting points for the development of chemical probes to investigate the cellular function of TRIM33. Identification of Histone Peptide Binding Specificity and Small-Molecule Ligands for the TRIM33alpha and TRIM33beta Bromodomains.,Sekirnik AR, Reynolds JK, See L, Bluck JP, Scorah AR, Tallant C, Lee B, Leszczynska KB, Grimley RL, Storer RI, Malattia M, Crespillo S, Caria S, Duclos S, Hammond EM, Knapp S, Morris GM, Duarte F, Biggin PC, Conway SJ ACS Chem Biol. 2022 Sep 13. doi: 10.1021/acschembio.2c00266. PMID:36098557[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Barker JJ | Caria S | Crespillo S | Duclos S | Errey J
