5ecj | pdb_00005ecj
Crystal structure of monobody Mb(S4) bound to Prdm14 in complex with Mtgr1
Structural highlights
DiseaseMTG8R_MOUSE Required for tumorigenesis in a AOM/DSS colitis-associated carcinoma model. May be involved in intestinal tumorigenesis.[1] FunctionPRD14_MOUSE Transcription factor that has both positive and negative roles on transcription. Plays a role in cellular pluripotency (By similarity). Essential for germ cell development at 2 levels: the reacquisition of potential pluripotency, including SOX2 up-regulation, and successful epigenetic reprogramming, characterized by EHMT1 repression.[2] MTG8R_MOUSE Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes. Via association with PRDM14 is involved in regulation of embryonic stem cell (ESC) pluripotency. Involved in primordial germ cell (PCG) formation (PubMed:27281218). Stabilizes PRDM14 and OCT4 on chromatin in a homooligomerization-dependent mannerCan repress the expression of MMP7 in a ZBTB33-dependent manner (By similarity). Through heteromerization with CBFA2T3/MTG16 may be involved in regulation of the proliferation and the differentiation of erythroid progenitors by repressing the expression of TAL1 target genes (PubMed:19799863). Required for the maintenance of the secretory cell lineage in the small intestine (PubMed:16227606). Can inhibit Notch signaling probably by association with RBPJ and may be involved in GFI1-mediated Paneth cell differentiation (PubMed:25398765).[UniProtKB:O43439][3] [4] [5] Publication Abstract from PubMedPrdm14 is a sequence-specific transcriptional regulator of embryonic stem cell (ESC) pluripotency and primordial germ cell (PGC) formation. It exerts its function, at least in part, through repressing genes associated with epigenetic modification and cell differentiation. Here, we show that this repressive function is mediated through an ETO-family co-repressor Mtgr1, which tightly binds to the pre-SET/SET domains of Prdm14 and co-occupies its genomic targets in mouse ESCs. We generated two monobodies, synthetic binding proteins, targeting the Prdm14 SET domain and demonstrate their utility, respectively, in facilitating crystallization and structure determination of the Prdm14-Mtgr1 complex, or as genetically encoded inhibitor of the Prdm14-Mtgr1 interaction. Structure-guided point mutants and the monobody abrogated the Prdm14-Mtgr1 association and disrupted Prdm14's function in mESC gene expression and PGC formation in vitro. Altogether, our work uncovers the molecular mechanism underlying Prdm14-mediated repression and provides renewable reagents for studying and controlling Prdm14 functions. ETO family protein Mtgr1 mediates Prdm14 functions in stem cell maintenance and primordial germ cell formation.,Nady N, Gupta A, Ma Z, Swigut T, Koide A, Koide S, Wysocka J Elife. 2015 Nov 2;4. pii: e10150. doi: 10.7554/eLife.10150. PMID:26523391[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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