3u5o

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Crystal structure of the complex of TRIM33 PHD-Bromo and H3(1-22)K9me3K14acK18ac histone peptide

Structural highlights

3u5o is a 16 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TRI33_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.

Function

TRI33_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 PubMed

Specific chromatin marks keep master regulators of differentiation silent yet poised for activation by extracellular signals. We report that nodal TGF-beta signals use the poised histone mark H3K9me3 to trigger differentiation of mammalian embryonic stem cells. Nodal receptors induce the formation of companion Smad4-Smad2/3 and TRIM33-Smad2/3 complexes. The PHD-Bromo cassette of TRIM33 facilitates binding of TRIM33-Smad2/3 to H3K9me3 and H3K18ac on the promoters of mesendoderm regulators Gsc and Mixl1. The crystal structure of this cassette, bound to histone H3 peptides, illustrates that PHD recognizes K9me3, and Bromo binds an adjacent K18ac. The interaction between TRIM33-Smad2/3 and H3K9me3 displaces the chromatin-compacting factor HP1gamma, making nodal response elements accessible to Smad4-Smad2/3 for Pol II recruitment. In turn, Smad4 increases K18 acetylation to augment TRIM33-Smad2/3 binding. Thus, nodal effectors use the H3K9me3 mark as a platform to switch master regulators of stem cell differentiation from the poised to the active state.

A Poised Chromatin Platform for TGF-beta Access to Master Regulators.,Xi Q, Wang Z, Zaromytidou AI, Zhang XH, Chow-Tsang LF, Liu JX, Kim H, Barlas A, Manova-Todorova K, Kaartinen V, Studer L, Mark W, Patel DJ, Massague J Cell. 2011 Dec 23;147(7):1511-24. PMID:22196728^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Venturini L, You J, Stadler M, Galien R, Lallemand V, Koken MH, Mattei MG, Ganser A, Chambon P, Losson R, de The H. TIF1gamma, a novel member of the transcriptional intermediary factor 1 family. Oncogene. 1999 Feb 4;18(5):1209-17. PMID:10022127 doi:http://dx.doi.org/10.1038/sj.onc.1202655
↑ Dupont S, Zacchigna L, Cordenonsi M, Soligo S, Adorno M, Rugge M, Piccolo S. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell. 2005 Apr 8;121(1):87-99. PMID:15820681 doi:http://dx.doi.org/S0092-8674(05)00107-8
↑ He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MA, Massague J. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell. 2006 Jun 2;125(5):929-41. PMID:16751102 doi:http://dx.doi.org/10.1016/j.cell.2006.03.045
↑ Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, Martello G, Stinchfield MJ, Soligo S, Morsut L, Inui M, Moro S, Modena N, Argenton F, Newfeld SJ, Piccolo S. FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell. 2009 Jan 9;136(1):123-35. doi: 10.1016/j.cell.2008.10.051. PMID:19135894 doi:http://dx.doi.org/10.1016/j.cell.2008.10.051
↑ Xi Q, Wang Z, Zaromytidou AI, Zhang XH, Chow-Tsang LF, Liu JX, Kim H, Barlas A, Manova-Todorova K, Kaartinen V, Studer L, Mark W, Patel DJ, Massague J. A Poised Chromatin Platform for TGF-beta Access to Master Regulators. Cell. 2011 Dec 23;147(7):1511-24. PMID:22196728 doi:10.1016/j.cell.2011.11.032