Chaperoned Ubiquitylation—Crystal Structures of the CHIP U Box E3 Ubiquitin Ligase and a CHIP-Ubc13-Uev1a Complex

Zhang, Minghao; Windheim, Mark; Roe, S. Mark; Peggie, Mark; Cohen, Philip; Prodromou, Chrisostomos; Pearl, Laurence H.

doi:10.1016/j.molcel.2005.09.023

Cited by 382 publications

(554 citation statements)

References 48 publications

Supporting

Mentioning

516

Contrasting

Unclassified

Order By: Relevance

“…CHIP is an E3 ligase that functions in ER and cytosolic protein quality control (Cyr et al 2002). CHIP consists of an amino-terminal tetratricopeptide (TPR) domain that binds to Hsc70, Hsp70, and Hsp90 molecular chaperones, a central helical domain mediating CHIP dimerization and a carboxy-terminal U-box domain responsible for binding E2-Ub-conjugating enzyme (Zhang et al 2005). A similar mechanism appears to be involved in the ubiquitindependent degradation of the unfolded mutant (DF508) CFTR with exposed misfolded cytosolic domains.…”

Section: Selection Of Damaged Pm Proteins For Ubiquitinationmentioning

confidence: 99%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

182

171

View full text Add to dashboard Cite

When ubiquitin (Ub) is attached to membrane proteins on the plasma membrane, it directs them through a series of sorting steps that culminate in their delivery to the lumen of the lysosome where they undergo complete proteolysis. Ubiquitin is recognized by a series of complexes that operate at a number of vesicle transport steps. Ubiquitin serves as a sorting signal for internalization at the plasma membrane and is the major signal for incorporation into intraluminal vesicles of multivesicular late endosomes. The sorting machineries that catalyze these steps can bind Ub via a variety of Ub-binding domains. At the same time, many of these complexes are themselves ubiquitinated, thus providing a plethora of potential mechanisms to regulate their activity. Here we provide an overview of how membrane proteins are selected for ubiquitination and deubiquitination within the endocytic pathway and how that ubiquitin signal is interpreted by endocytic sorting machineries. HOW PROTEINS ARE SELECTED FOR UBIQUITINATIONU biquitin (Ub) is covalently attached to substrate proteins by the concerted action of E2-conjugating enzymes and E3 ligases (Varshavsky 2012). Most of the specificity and regulation of ubiquitination is at the level of the E3 ligases, which vastly outnumber the E2-conjugating enzymes. Ubiquitination results from the transfer of Ub, held either by the E2 or in some cases by the E3 as a high-energy thioester bond, onto a substrate protein, typically on the terminal amide of a substrate acceptor lysine side chain. Owing to the intense interest in the ubiquitination system, many of the simple rules and distinctions concerning different types of ligases, their specificity for forming particular polyUb chains, and even the kinds of residues in substrate proteins that can be ubiquitin modified, have been blurred with the discovery of mixed poly-Ub chains, new enzymatic mechanisms for Ub transfer, and ubiquitination of nonlysine residues (Kulathu and Komander 2012;Wenzel and Klevit 2012;McDowell and Philpott 2013). Nonetheless, in basic terms, Ub ligases function as platforms that coordinate substrate recognition with Ub transfer as well as configuring poly-Ub chain topology by the E2-conjugating enzyme. Substrates can be bound directly by the E3 ligase or by adaptor proteins that in turn bind to ligases, and selecEditors:

show abstract

Section: Selection Of Damaged Pm Proteins For Ubiquitinationmentioning

confidence: 99%

Ubiquitin-Dependent Sorting in Endocytosis

Piper

Đikić

Lukacs

2014

Cold Spring Harbor Perspectives in Biology

182

171

View full text Add to dashboard Cite

show abstract

“…CHIP was shown to possess an E3 ubiquitin ligase activity [69,70] and has been implicated in ubiquitination and proteasomal targeting of a variety of proteins, such as transcription factors SMAD and E2A [71,72] and nitric oxide synthase [73,74]. CHIP was also found to be able to promote formation of Lys63-linked polyubiquitin chains in collaboration with Uev1a-Ubc13 in vitro [75]. In plants, the Arabidopsis CHIP gene AtCHIP is upregulated upon temperature stress [76].…”

Section: U-box-type E3 Ligases Are Newly Identified Members Of the Ubmentioning

confidence: 99%

Ubiquitination-mediated protein degradation and modification: an emerging theme in plant-microbe interactions

et al. 2006

View full text Add to dashboard Cite

Post-translational modification is central to protein stability and to the modulation of protein activity. Various types of protein modification, such as phosphorylation, methylation, acetylation, myristoylation, glycosylation, and ubiquitination, have been reported. Among them, ubiquitination distinguishes itself from others in that most of the ubiquitinated proteins are targeted to the 26S proteasome for degradation. The ubiquitin/26S proteasome system constitutes the major protein degradation pathway in the cell. In recent years, the importance of the ubiquitination machinery in the control of numerous eukaryotic cellular functions has been increasingly appreciated. Increasing number of E3 ubiquitin ligases and their substrates, including a variety of essential cellular regulators have been identified. Studies in the past several years have revealed that the ubiquitination system is important for a broad range of plant developmental processes and responses to abiotic and biotic stresses. This review discusses recent advances in the functional analysis of ubiquitination-associated proteins from plants and pathogens that play important roles in plant-microbe interactions.

show abstract

“…The U-box domain plays a key role in targeting proteins for ubiquitinylation and subsequent proteasome-dependent degradation. 16,17 On the other hand, STUB1 is known to be a bona fide interaction partner of the major cytoplasmic chaperones HSPA8 and HSPA4, through its TPR domain. 18,19 STUB1 has been shown to target several substrates for the UPS, including immature CFTR/cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7), 20 ERBB2/v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) 21 and SNCA/α-synuclein.…”

Section: Introductionmentioning

confidence: 99%

STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy

Fofo²,

et al. 2013

View full text Add to dashboard Cite

The transcription factor hiF1 is mostly regulated by the oxygen-dependent proteasomal degradation of the labile subunit hiF1A. recent data showed degradation of hiF1A in the lysosome through chaperone-mediated autophagy (cMA). however the molecular mechanism involved has not been elucidated. This study shows that the KFerQ-like motif, that has been identified in all cMA substrates, is required to mediate the interaction between hiF1A and the chaperone hSpA8. Moreover, mutations in the KFerQ-like motif of hiF1A preclude the interaction with the cMA receptor LAMp2A, thus inhibiting its lysosomal degradation. importantly, we show for the first time that the ubiquitin ligase STUB1 is required for degradation of hiF1A in the lysosome by cMA. indeed, mutations in STUB1 that inhibit either the ubiquitin ligase activity or its ability to bind to hSpA8, both prevent degradation of hiF1A by cMA. Moreover, we show that hiF1A binds to and is translocated into intact lysosomes isolated from rat livers. This new pathway for degradation of hiF1A does not depend on the presence of oxygen and is activated in response to nutrient deprivation such that the levels of hiF1A bound to cMA positive lysosomes significantly increase in starved animal livers and the binding of hiF1A to LAMp2A increases in response to serum deprivation. Moreover, excessive degradation of hiF1A by cMA compromises cells' ability to respond to and survive under hypoxia, suggesting that this pathway might be of pathophysiological importance in conditions that combine hypoxia with starvation. leucinylleucinylleucinal/proteasome inhibitor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; RCC, renal cell carcinoma; Serpinb, serpin peptidase inhibitor, clade B/Ovalbumin; SLC2A1, solute carrier family 2 (facilitated glucose transporter)/glucose transporter; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; UPS, ubiquitin-proteasome system; VEGFA, vascular endothelial growth factor A; u-box, modified RING finger domain lacking the metal-chelating residues

show abstract

Chaperoned Ubiquitylation—Crystal Structures of the CHIP U Box E3 Ubiquitin Ligase and a CHIP-Ubc13-Uev1a Complex

Cited by 382 publications

References 48 publications

Ubiquitin-Dependent Sorting in Endocytosis

Ubiquitin-Dependent Sorting in Endocytosis

Ubiquitination-mediated protein degradation and modification: an emerging theme in plant-microbe interactions

STUB1/CHIP is required for HIF1A degradation by chaperone-mediated autophagy

Contact Info

Product

Resources

About