PDF《Ubiquitin-binding domains》

Biochem.

J. (2006) 399, 361C372 (Printed in Great Britain) doi:10.1042/BJ20061138

361 REVIEW ARTICLE Ubiquitin-binding domains James H. HURLEY1 , Sangho LEE and Gali PRAG Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD 20892, U.S.A. The covalent modi?cation of proteins by ubiquitination is a major regulatory mechanism of protein degradation and quality control, endocytosis, vesicular traf?cking, cell-cycle control, stress res- ponse, DNA repair, growth-factor signalling, transcription, gene silencing and other areas of biology. A class of speci?c ubiquitin- binding domains mediates most of the effects of protein ubiquit- ination. The known membership of this group has expanded rapidly and now includes at least sixteen domains: UBA, UIM, MIU, DUIM, CUE, GAT, NZF, A20 ZnF, UBP ZnF, UBZ, Ubc, UEV, UBM, GLUE, Jab1/MPN and PFU. The structures of many of the complexes with mono-ubiquitin have been determined, revealing interactions with multiple surfaces on ubiquitin. Inroads into understanding polyubiquitin speci?city have been made for two UBA domains, whose structures have been characterized in complex with Lys48 -linked di-ubiquitin. Several ubiquitin- binding domains, including the UIM, CUE and A20 ZnF (zinc ?nger) domains, promote auto-ubiquitination, which regulates the activity of proteins that contain them. At least one of these domains, the A20 ZnF, acts as a ubiquitin ligase by recruiting a ubiquitinCubiquitin-conjugating enzyme thiolester adduct in a process that depends on the ubiquitin-binding activity of the A20 ZnF. The af?nities of the mono-ubiquitin-binding interactions of these domains span a wide range, but are most commonly weak, with Kd>

100 ?M. The weak interactions between individual domains and mono-ubiquitin are leveraged into physiologically relevant high-af?nity interactions via several mechanisms: ubi- quitin polymerization, modi?cation multiplicity, oligomerization of ubiquitinated proteins and binding domain proteins, tandem- binding domains, binding domains with multiple ubiquitin-bind- ing sites and co-operativity between ubiquitin binding and binding through other domains to phospholipids and small G-proteins. Key words: endocytosis, proteasome, protein structure, ubiquit- ination, ubiquitin-binding domain, vesicle traf?cking. UBIQUITIN AND PROTEIN UBIQUITINATION Ubiquitin is a 76-amino-acid protein (Figure 1), so-named for its extraordinarily wide distribution from yeast to man [1]. The covalent ubiquitination of proteins is a widespread regulatory post-translational modi?cation, much like protein phosphoryl- ation. The C-terminus of ubiquitin is conjugated to lysine residues of target proteins by the action of three enzymes: an ubiquitin- activating enzyme (E1), an ubiquitin-conjugating enzyme (E2) and an ubiquitin protein ligase (E3) (Figure 2) [1C4]. Ubiquitin is conjugated to proteins via an isopeptide bond between the C- terminus of ubiquitin and speci?c lysine residues in the ubiquit- inated protein. Ubiquitin may be attached to proteins as a mono- mer or as a polyubiquitin chain. Ubiquitin polymers are formed when additional ubiquitin molecules are attached to lysine residues on a previously attached ubiquitin. Early interest in ubiquitination centred on the role of poly- ubiquitin chains in targeting proteins for degradation by the

26 S proteasome [5,6]. We now know that ubiquitination regu- lates a much wider array of cell processes, including endocytosis, vesicular traf?cking [7C9], cell-cycle control, stress response, DNA repair [10], signalling [11,12], transcription and gene silencing. Recent progress in the discovery of new biological roles for ubiquitination has gone hand in hand with the discovery of a host of ubiquitin-binding domains [13,14] (Table 1). The char- acterization of these domains has become a major foundation for advancing the biology of ubiquitin-based regulatory mechanisms. UBIQUITIN-BINDING DOMAINS: STRUCTURE AND FUNCTION Helical domains The largest class of ubiquitin-binding domains are α-helical: UBA (ubiquitin associated), UIM (ubiquitin-interacting motif), DUIM (double-sided UIM), MIU (motif interacting with ubiquitin), CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) and GAT [GGA (Golgi-localized, gamma-ear- containing, ADP-ribosylation-factor-binding protein) and TOM (target of Myb)]. All of the helical ubiquitin-binding domains are known to interact with a single region on ubiquitin, the Ile44 hydrophobic patch. The UBA and CUE domains have structural homology, with a common three-helical bundle architecture. They also have similar modes of binding to the Ile44 patch. The UIM and GAT domain structures are unrelated, except for being helical, and they interact with this patch in different ways (Figure 3). The otherwise unrelated octahelical VHS [Vps (vacuolar sorting protein) 27/Hrs/STAM] domain has also been reported to bind to ubiquitin [15]. UIM The UIM is found in many traf?cking proteins that recognize ubiquitinated cargo, the S5a subunit of the proteasome and other proteins [16C21]. Many UIMs have been shown to promote the ubiquitination of proteins that contain them [17C19,21C24]. UIMs Abbreviations used: CUE, coupling of ubiquitin conjugation to endoplasmic reticulum degradation;