Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

More documents

Recommendations

Info

Introduction – among them BRUCE, a 528 kDa inhibitor of apoptosis (Hauser et al., 1998) – most E2s are of rather small size (Jentsch et al., 1990). Two different E1 enzymes are able to activate ubiquitin in the first step of the ubiquitin conjugation process. These ubiquitin-activating enzymes, which are called UBE1 and UBA6, serve distinct, but overlapping pools of E2s. Although both E1s are broadly expressed in all tissue types, deletion of either one of them is lethal, indicating that there is little redundancy in the system. Interestingly, UBE1 – which was long thought to be the only ubiquitin-conjugating enzyme in existence – is expressed at a much higher level in most tissues and accounts for up to 85% of all ubiquitin conjugates observed (Groettrup et al., 2008). A further layer of complexity is added to the ubiquitin-system through the actions of a group of deubiquitylating enzymes, or DUBs, the majority of which fall into one of two subgroups: The family of ubiquitin C-terminal hydrolases (UCHs) or the family of ubiquitin-specific processing proteases (UBPs). DUBs carry out a variety of processing or editing functions. Some of them are responsible for the processing of linear ubiquitin-fusions and are required for the generation of ac- tive ubiquitin from newly synthesized precursor proteins. Others are responsible for the removal of polyubiquitin-chains from proteins targeted for proteasomal degradation, ensuring that these are not degraded along with their substrates but instead recycled. Once the ubiquitin chains are liberated, a second group of DUBs then disassembles them into ubiquitin monomers. Yet another group is involved in the modulation of various ubiquitin signals. They can, for example, res- cue proteins from degradation by removing their ubiquitin-tags before they come into contact with the proteasome, or attenuate signal transduction cascades by removing the activating K63-linked chains (Amerik and Hochstrasser, 2004). Both the enzymes involved in ubiquitin-processing as well as the effector proteins which act downstream of the ubiquitin signal need to interact with ubiquitin, and this recognition is mediated by a plethora of different ubiquitin-binding domains. These include – but may not be limited to – sixteen different domains: UBA, UIM, MIU, DUIM, CUE, GAT, NZF, A20 ZnF, BUZ, UBZ, Ubc, UEV, UBM, GLUE, Jab1/MPN and PFU. Interestingly, although several of these domains display absolutely no sequence similarity and seem to have evolved independently of each other, most of them bind to ubiquitin through a conserved surface encom- passing residues Leu8, Ile44 and Val70, which is called the “hydrophobic patch”. A notable exception to this rule is the BUZ domain, a zinc-finger which instead interacts with ubiquitin through its free C-terminal diglycine-motif, and is for 17
Introduction example contained in the deubiquitylating enzyme isopeptidase T or the tubulin deacetylase HDAC6. Most ubiquitin-binding domains display a preference for either monoubiquitin, different polyubiquitin chain topologies or ubiquitin-like domains, although the exact molecular determinants of this ability to discriminate remain unknown (Hurley et al., 2006). Ubiquitin-Like Proteins All eukaryotic cells contain several additional proteins which are related to ubiquitin in either sequence or structure. Like ubiquitin, these proteins are involved in a vast number of fundamental cellular processes. Collectively known as ubiquitin-like proteins, they can be subdivided into the families of ubiquitin- like modifiers and ubiquitin-domain proteins (Fig. 3). Members of the first group function – as their name suggests – as modifiers, and are covalently attached to other proteins in a manner analogous to ubiquitin conjugation. Members of the second group are larger proteins and contain a ubiquitin-like domain as an in- tegral part of their sequence, but are otherwise functinally diverse (Jentsch and Pyrowolakis, 2000). Ubiquitin-Like Modifiers With the exception of ATG8, ATG12 and URM1, all ubiquitin-like modifiers (UbLs) display a high level of sequence homology to ubiquitin and, regardless of their sequence, they all share essentially the same three-dimensional structure. In addition, those UbLs which are capable of covalent attachment to another protein invariably share a conserved glycine residue at their C-terminus, and the carboxyl group of this glycine is the site of attachment to their substrates. Like ubiquitin, most of them are generated as precursors with C-terminal exten- sions of variing length and need to be activated through endoproteolytic processing. This step is mediated by UbL-specific proteases (ULPs), which function in a manner analogous to DUBs and are also capable of hydrolizing the isopeptide bond between their specific UbL and its target proteins. Exceptions to this rule are ATG12, URM1 and FAT10, which already contain a free glycine at their C- terminus and have no requirement for processing. Ubiquitin-like modifiers are also conjugated to their target proteins by way of a multi-enzyme cascade, in a manner analogous to that of ubiquitin conjugation, 18
Page 1 and 2: Role of the ubiquitin-like modifier
Page 3 and 4: Acknowledgements . . . . . . . . .
Page 5 and 6: Summary / Zusammenfassung English F
Page 7 and 8: Summary In conclusion, these result
Page 9 and 10: Summary nicht von der katalytischen
Page 11 and 12: The Ubiquitin-Proteasome-System The
Page 13 and 14: Introduction Figure 1: The 26S prot
Page 15 and 16: Introduction are the major source o
Page 17: Introduction majority of ubiquitin-
Page 21 and 22: Introduction two modifiers apart fr
Page 23 and 24: Introduction Figure 4: Comparison o
Page 25 and 26: Introduction dependent apoptosis in
Page 27 and 28: Introduction Interestingly, a recen
Page 29 and 30: The Autophagy-Lysosome System Intro
Page 31 and 32: Introduction Figure 5: Molecular ma
Page 33 and 34: Introduction The transport of misfo
Page 35 and 36: Introduction where the proteasome i
Page 37 and 38: Chapter 1 The UBA domains of NUB1L
Page 39 and 40: Introduction Chapter 1 Ubiquitin, a
Page 41 and 42: Chapter 1 no correlation between th
Page 43 and 44: Chapter 1 covered proteins were sep
Page 45 and 46: Chapter 1 Figure 8: Accelerated deg
Page 47 and 48: Chapter 1 Treatment with IFN-γ and
Page 49 and 50: Chapter 1 ing SUMO-1-GFP or the C-t
Page 51 and 52: Chapter 1 Figure 12: Accelerated de
Page 53 and 54: Chapter 1 Figure 13: Co-immunopreci
Page 55 and 56: Chapter 1 domains of NUB1L is requi
Page 57 and 58: Chapter 1 Rad23 (Verma et al., 2004
Page 59 and 60: Chapter 1 FAT10-GFP expressing vect
Page 61 and 62: Chapter 2 Degradation of FAT10 by t
Page 63 and 64: Introduction Chapter 2 The proteaso
Page 65 and 66: Chapter 2 From our previous data it
Page 67 and 68: Chapter 2 Figure 14: Purified compo
Page 69 and 70:
Chapter 2 evaluation of the NUB1L b
Page 71 and 72:
Chapter 2 teins which contain intri
Page 73 and 74:
Chapter 2 Combined with our studies
Page 75 and 76:
Chapter 2 Recombinant expression of
Page 77 and 78:
Chapter 2 et al., 2003), both at a
Page 79 and 80:
Abstract Chapter 3 During misfolded
Page 81 and 82:
Chapter 3 tion between the UPS and
Page 83 and 84:
Chapter 3 Figure 18: HDAC6 interact
Page 85 and 86:
Chapter 3 Figure 19: Both the BUZ d
Page 87 and 88:
Chapter 3 of HDAC6 was required for
Page 89 and 90:
Chapter 3 precipitates with HDAC6 (
Page 91 and 92:
90 Chapter 3
Page 93 and 94:
Chapter 3 Figure 23: The model conj
Page 95 and 96:
Chapter 3 HDAC6 is required for the
Page 97 and 98:
Chapter 3 Figure 26: Both ubiquitin
Page 99 and 100:
Chapter 3 also revealed endogenous,
Page 101 and 102:
Chapter 3 and/or its conjugates is
Page 103 and 104:
Chapter 3 (Hipp et al., 2005), pEGF
Page 105 and 106:
Chapter 4 FAT10-deficient mice disp
Page 107 and 108:
Chapter 4 Once the infection is cle
Page 109 and 110:
Chapter 4 As both wild-type as well
Page 111 and 112:
Chapter 4 Peptides. The synthetic p
Page 113 and 114:
Introduction Chapter 5 Antibodies a
Page 115 and 116:
Chapter 5 binant human and mouse GS
Page 117 and 118:
Chapter 5 Figure 34: The antibodies
Page 119 and 120:
Chapter 5 Figure 36: The antibody s
Page 121 and 122:
Discussion 30 years ago, ubiquitin
Page 123 and 124:
Discussion monomeric ubiquitin as w
Page 125 and 126:
Discussion Alternatively, FAT10 cou
Page 127 and 128:
References D. T. Akey, X. Zhu, M. D
Page 129 and 130:
References Y.-H. Chiu, Q. Sun, and
Page 131 and 132:
References S. Gunawardena, L.-S. He
Page 133 and 134:
References J. A. Johnston, M. E. Il
Page 135 and 136:
References F. Lévy, N. Johnsson, T
Page 137 and 138:
References J.-H. Park, H.-S. Jong,
Page 139 and 140:
References P. Schreiner, X. Chen, K
Page 141 and 142:
References S. Vijay-Kumar, C. E. Bu
Page 143 and 144:
Abbreviations aa amino acid AAA ATP
Page 145 and 146:
Amino Acids Alanine Ala A Arginine
show all

Role of the ubiquitin-like modifier FAT10 in protein degradation and ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?