Anatomy of the E2 ligase fold: Implications for enzymology and evolution of ubiquitin/Ub-like protein conjugation

被引:91
作者
Burroughs, A. Maxwell [1 ,2 ]
Jaffee, Marcie [1 ]
Iyer, Lakshminarayan M. [1 ]
Aravind, L. [1 ]
机构
[1] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA
[2] Boston Univ, Bioinformat Program, Boston, MA 02215 USA
基金
美国国家卫生研究院;
关键词
ubiquitin; ligation; trans-thiolation; E2; E1; active site; UBC; RWD; ubiquitin-conjugation; enzyme evolution; cataysis;
D O I
10.1016/j.jsb.2007.12.006
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The configuration of the active site of E2 ligases, central enzymes in the ubiquitin/ubiquitin-like protein (Ub/Ub2) conjugation systems, has long puzzled researchers. Taking advantage of the wealth of newly available structures and sequences of E2s from diverse organisms, we performed a large-scale comparative analysis of these proteins. As a result we identified a previously under-appreciated diversity in the active site of these enzymes, in particular, the spatial location of the catalytic cysteine and a constellation of associated conserved residues that potentially contributes to catalysis. We observed structural innovations of differing magnitudes occurring in various families across the E2 fold that might correlate in part with differences in target interaction. A key finding was the independent emergence on multiple occasions of a polar residue, often a histidine, in the vicinity of the catalytic cysteine in different E2 families. We propose that these convergently emerging polar residues have a common function, such as in the stabilization of oxyanion holes during Ub/Ub1 transfer and spatial localization of the Ub/Ub1 tails in the active site. Thus, the E2 ligases represent a rare example in enzyme evolution of high structural diversity of the active site and position of the catalytic residue despite all characterized members catalyzing a similar reaction. Our studies also indicated certain evolutionarily conserved features in all active members of the E2 superfamily that stabilize the unusual flap-like structure in the fold. These features are likely to form a critical mechanical element of the fold required for catalysis. The results presented here could aid in new experiments to understand E2 catalysis. Published by Elsevier Inc.
引用
收藏
页码:205 / 218
页数:14
相关论文
共 59 条
[41]   The role of lineage-specific gene family expansion in the evolution of eukaryotes [J].
Lespinet, O ;
Wolf, YI ;
Koonin, EV ;
Aravind, L .
GENOME RESEARCH, 2002, 12 (07) :1048-1059
[42]   SUMO: ligases, isopeptidases and nuclear pores [J].
Melchior, F ;
Schergaut, M ;
Pichler, A .
TRENDS IN BIOCHEMICAL SCIENCES, 2003, 28 (11) :612-618
[43]   Demonstration of ubiquitin thiolester formation of UBE2Q2 (UBCi), a novel ubiquitin-conjugating enzyme with implantation site-specific expression [J].
Melner, Michael H. ;
Haas, Arthur L. ;
Klein, Jennifer M. ;
Brash, Alan R. ;
Boeglin, William E. ;
NagDas, Subir K. ;
Winfrey, Virginia P. ;
Olson, Gary E. .
BIOLOGY OF REPRODUCTION, 2006, 75 (03) :395-406
[44]   Crystal structure of Ufc1, the Ufm1-conjugating enzyme [J].
Mizushima, Tsunehiro ;
Tatsumi, Kanako ;
Ozaki, Yoko ;
Kawakami, Tatsukuni ;
Suzuki, Atsuo ;
Ogasahara, Kyoko ;
Komatsu, Masaaki ;
Kominami, Eiki ;
Tanaka, Keiji ;
Yamane, Takashi .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2007, 362 (04) :1079-1084
[45]   Crystal structure of the human ubiquitin conjugating enzyme complex, hMms2-hUbc13 [J].
Moraes, TF ;
Edwards, RA ;
McKenna, S ;
Pastushok, L ;
Xiao, W ;
Glover, JNM ;
Ellison, MJ .
NATURE STRUCTURAL BIOLOGY, 2001, 8 (08) :669-673
[46]   SCOP - A STRUCTURAL CLASSIFICATION OF PROTEINS DATABASE FOR THE INVESTIGATION OF SEQUENCES AND STRUCTURES [J].
MURZIN, AG ;
BRENNER, SE ;
HUBBARD, T ;
CHOTHIA, C .
JOURNAL OF MOLECULAR BIOLOGY, 1995, 247 (04) :536-540
[47]   Solution structure of the RWD domain of the mouse GCN2 protein [J].
Nameki, N ;
Yoneyama, M ;
Koshiba, S ;
Tochio, N ;
Inoue, M ;
Seki, E ;
Matsuda, T ;
Tomo, Y ;
Harada, T ;
Saito, K ;
Kobayashi, N ;
Yabuki, T ;
Aoki, M ;
Nunokawa, E ;
Matsuda, N ;
Sakagami, N ;
Terada, T ;
Shirouzu, M ;
Yoshida, M ;
Hirota, H ;
Osanai, T ;
Tanaka, A ;
Arakawa, T ;
Carninci, P ;
Kawai, J ;
Hayashizaki, Y ;
Kinoshita, K ;
Güntert, P ;
Kigawa, T ;
Yokoyama, S .
PROTEIN SCIENCE, 2004, 13 (08) :2089-2100
[48]   Mechanisms underlying ubiquitination [J].
Pickart, CM .
ANNUAL REVIEW OF BIOCHEMISTRY, 2001, 70 :503-533
[49]  
RAWLINGS ND, 1994, METHOD ENZYMOL, V244, P461
[50]   Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex [J].
Reverter, D ;
Lima, CD .
NATURE, 2005, 435 (7042) :687-692