6bhi
From Proteopedia
Crystal structure of SETDB1 with a modified H3 peptide
Structural highlights
FunctionSETB1_HUMAN Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 'Lys-9' trimethylation is coordinated with DNA methylation. Probably forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins.[1] [2] [3] [4] Publication Abstract from PubMedSETDB1 is an essential H3K9 methyltransferase involved in silencing of retroviruses and gene regulation. We show here that its triple Tudor domain (3TD) specifically binds to doubly modified histone H3 containing K14 acetylation and K9 methylation. Crystal structures of 3TD in complex with H3K14ac/K9me peptides reveal that peptide binding and K14ac recognition occurs at the interface between Tudor domains (TD) TD2 and TD3. Structural and biochemical data demonstrate a pocket switch mechanism in histone code reading, because K9me1 or K9me2 is preferentially recognized by the aromatic cage of TD3, while K9me3 selectively binds to TD2. Mutations in the K14ac/K9me binding sites change the sub-nuclear localization of 3TD. ChIP-seq analyses show that SETDB1 is enriched at H3K9me3 regions and K9me3/K14ac is enriched at SETDB1 binding sites overlapping with LINE elements, suggesting that recruitment of the SETDB1 complex to K14ac/K9me regions has a role in silencing of active genomic regions. H3K14ac is linked to methylation of H3K9 by the triple Tudor domain of SETDB1.,Jurkowska RZ, Qin S, Kungulovski G, Tempel W, Liu Y, Bashtrykov P, Stiefelmaier J, Jurkowski TP, Kudithipudi S, Weirich S, Tamas R, Wu H, Dombrovski L, Loppnau P, Reinhardt R, Min J, Jeltsch A Nat Commun. 2017 Dec 12;8(1):2057. doi: 10.1038/s41467-017-02259-9. PMID:29234025[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
Categories: Homo sapiens | Large Structures | Arrowsmith CH | Bountra C | Edwards AM | Min J | Qin S | Tempel W
