The OTU domain deubiquitinase TRABID specifically hydrolyzes atypical Lys29- and Lys33-linked diubiquitin chains. Structural analysis of TRABID reveals an unpredicted ankyrin-repeat domain that binds ubiquitin and is crucial for TRABID efficiency and linkage specificity in vitro and in vivo.
Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles1, 2. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target3. Here we describe the small...
The Saccharomyces cerevisiae proteasome comprises a 19-subunit regulatory particle and a 28-subunit core particle. To be degraded, substrates must cross the core particle–regulatory particle interface, a site for complex conformational changes and regulatory events. This interface includes two aligned heteromeric rings, one formed by the six...
Protein degradation by the 26S proteasome is a fundamental process involved in a broad range of cellular activities, yet how proteasome activity is regulated remains poorly understood. We report here that ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) is a 26S proteasome phosphatase that regulates nuclear proteasome...
In response to viral infection, RIG-I-like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-
B to induce type I interferons. We have previously shown that RIG-I binds to unanchored...
Several mechanisms have been proposed for the synthesis of substrate-linked ubiquitin chains. HECT ligases directly catalyse protein ubiquitination and have been found to non-covalently interact with ubiquitin. We report crystal structures of the Nedd4 HECT domain, alone and in complex with ubiquitin, which show a new binding mode...
The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function...
Deubiquitinating enzymes (DUbs) play important roles in many ubiquitin-dependent pathways, yet how DUbs themselves are regulated is not well understood. Here, we provide insight...
Pax-6 is an evolutionarily conserved transcription factor regulating brain and eye development. Four Pax-6 isoforms have been reported previously. Although the longer Pax-6 isoforms (p46 and p48)...
Only one drug targeting the proteasome protein degradation pathway has been approved, but several second-generation inhibitors are making progress in trials. Jim Kling reports.
In July, Onyx Pharmaceuticals of Emeryville, California, announced positive phase 2...
An efficient linear solid-phase peptide synthesis of ubiquitin (Ub) has been developed. This approach allows the incorporation of desired tags and mutations (see picture; blue denotes a pseudoproline dipeptide, red a dimethoxybenzyl dipeptide) as well as specific C-terminal modification and the construction of all diubiquitin conjugates in high...
Polyubiquitin chains mediate a variety of biological processes,ranging from proteasomal targeting to inflammatory signalingand DNA repair. Their functional diversity is in part due to theirability to adopt distinct conformations, depending on how theubiquitin moieties within the chain are linked. We have usedthe eukaryotic replication clamp...
Conjugates of ubiquitin or itshomologues to other proteins occur bystrictly ordered steps with orderedaddition of substrates for each step.High concentrations of E2 were shownto inhibit the formation of E2~Ublthioester and Ubl~target conjugates.We investigated the mechanism ofsuch inhibitory effect of the SUMO E2,and whether the E2 has two...
Cancer Res; 70(15); 6384–92. ©2010 AACR.The breast cancer suppressor BRCA1 forms a stable heterodimeric E3 ubiquitin ligase with BARD1. Eachprotein controls the abundance and stability of the other, and loss of the interaction leads to BRCA1 degradation.Here, we show that HERC2, a protein recently implicated in DNA damage repair, targets...
It has become increasingly clear that cellular proteins can become conjugated with chains of the small proteinubiquitin without becoming degraded by the proteasome. This "noncanonical" process allows ubiquitinated proteins to regulate numerous processes including DNA repair and cell signaling. However, determining the mechanisms by which...
Terminally misfolded proteins that accumulate in the endoplasmic reticulum (ER) are dislocated and targeted for ubiquitin-dependent destruction by the proteasome. UBC6e is a tail-anchored E2 ubiquitin-conjugating enzyme that is part of a dislocation complex nucleated by the ER-resident protein SEL1L. Little is known about the turnover of tail-...
RIG-I detects invading viral RNA and activates the transcription factors NF-kappaB and IRF3 through the mitochondrial protein MAVS. Here we show that RNA bearing 5'-triphosphate strongly activates the RIG-I-IRF3 signaling cascade in a reconstituted system...
The PTEN (phosphatase and tensin homolog) tumor suppressor is a phosphatase that inhibits phosphoinositide 3-kinase-dependent signaling by metabolizing the phosphoinositide lipid phosphatidylinositol 3,4,5-trisphosphate (PtdInsP(3)) at the plasma membrane. PTEN can be mono- or polyubiquitinated, and this appears to control its nuclear...
Deubiquitinases (DUBs) are emerging as important regulators of many pathways germane to cancer. They may regulate the stability of key oncogenes, exemplified by USP28 stabilisation of c-Myc. Alternatively they can negatively regulate ubiquitin-dependent signalling cascades such as the NF-B activation pathway. We review the current literature...
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