6aqr
SAGA DUB module Ubp8(C146A)/Sgf11/Sus1/Sgf73 bound to monoubiquitin
Structural highlights
FunctionSUS1_YEAST Involved in mRNA export coupled transcription activation by association with both the TREX-2 and the SAGA complexes. The transcription regulatory histone acetylation (HAT) complex SAGA is involved in RNA polymerase II-dependent regulation of approximately 10% of yeast genes. At the promoters, SAGA is required for recruitment of the basal transcription machinery. It influences RNA polymerase II transcriptional activity through different activities such as TBP interaction (SPT3, SPT8 and SPT20) and promoter selectivity, interaction with transcription activators (GCN5, ADA2, ADA3 and TRA1), and chromatin modification through histone acetylation (GCN5) and deubiquitination (UBP8). SUS1 forms a distinct functional SAGA module with UBP8, SGF11 and SGF73 required for deubiquitination of H2B and for the maintenance of steady-state H3 methylation levels. The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket), by association with components of the nuclear mRNA export machinery (MEX67-MTR2 and SUB2) in the nucleoplasm and the nucleoporin NUP1 at the nuclear basket. TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. SUS1 has also a role in mRNP biogenesis and maintenance of genome integrity through preventing RNA-mediated genome instability. Finally SUS1 has a role in response to DNA damage induced by methyl methane sulfonate (MMS) and replication arrest induced by hydroxyurea.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedA common strategy for exploring the biological roles of deubiquitinating enzymes (DUBs) in different pathways is to study the effects of replacing the wild-type DUB with a catalytically inactive mutant in cells. We report here that a commonly studied DUB mutation, in which the catalytic cysteine is replaced with alanine, can dramatically increase the affinity of some DUBs for ubiquitin. Overexpression of these tight-binding mutants thus has the potential to sequester cellular pools of monoubiquitin and ubiquitin chains. As a result, cells expressing these mutants may display unpredictable dominant negative physiological effects that are not related to loss of DUB activity. The structure of the SAGA DUB module bound to free ubiquitin reveals the structural basis for the 30-fold higher affinity of Ubp8(C146A) for ubiquitin. We show that an alternative option, substituting the active site cysteine with arginine, can inactivate DUBs while also decreasing the affinity for ubiquitin. Active site alanine mutations convert deubiquitinases into high-affinity ubiquitin-binding proteins.,Morrow ME, Morgan MT, Clerici M, Growkova K, Yan M, Komander D, Sixma TK, Simicek M, Wolberger C EMBO Rep. 2018 Aug 27. pii: embr.201745680. doi: 10.15252/embr.201745680. PMID:30150323[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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