Crystal structure of a vFlip-IKKγ complex:: Insights into viral activation of the IKK signalosome

被引:95
作者
Bagneris, Claire [1 ]
Ageichik, Alexander V. [2 ]
Cronin, Nora [1 ]
Wallace, Bonnie [1 ]
Collins, Mary [2 ]
Boshoff, Chris [3 ]
Waksman, Gabriel [1 ]
Barrett, Tracey [1 ]
机构
[1] Birkbeck Coll, Sch Crystallog, Inst Struct & Mol Biol, London WC1E 7HX, England
[2] UCL, Div Infect & Immun, London W1T 4JF, England
[3] UCL, Inst Canc, Canc Res UK Virol Oncol Grp, London WC1E 6BT, England
基金
英国医学研究理事会;
关键词
D O I
10.1016/j.molcel.2008.04.029
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
Key to the pathogenicity of several viruses is activation of the canonical nuclear factor-kappa B (NF-kappa B) transcriptional pathway. Subversion of this tightly regulated mechanism is achieved through the production of host mimetic viral proteins that deregulate the transcription process. One such protein is ks-vFLIP (produced by the Kaposi's sarcoma herpes virus [KSHV]), which associates with IKK gamma, an essential component of the IKK complex or signalosome. This interaction renders the canonical NF-kappa B pathway constitutively active and has been linked to Kaposi's sarcoma and other malignancies. In order to elucidate the molecular basis underpinning ks-vFLIP-induced activation of the IKK signalosome, we have determined the crystal structure of a complex involving a fragment of IKK gamma bound to ks-vFLIP at 3.2 angstrom. In addition to identifying and subsequently probing the ks-vFLIP-IKK gamma interface, we have also investigated the effects of a mutation implicated in the genetic disorder anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID).
引用
收藏
页码:620 / 631
页数:12
相关论文
共 49 条
[1]   The trimerization domain of nemo is composed of the interacting C-terminal CC2 and LZ coiled-coil subdomains [J].
Agou, F ;
Traincard, F ;
Vinolo, E ;
Courtois, G ;
Yamaoka, S ;
Israël, A ;
Véron, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (27) :27861-27869
[2]   NEMO trimerizes through its coiled-coil C-terminal domain [J].
Agou, F ;
Ye, F ;
Goffinont, S ;
Courtois, G ;
Yamaoka, S ;
Israël, A ;
Véron, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (20) :17464-17475
[3]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[4]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[5]   KAPOSIS SARCOMA-ASSOCIATED HERPESVIRUS-LIKE DNA-SEQUENCES IN AIDS-RELATED BODY-CAVITY-BASED LYMPHOMAS [J].
CESARMAN, E ;
CHANG, Y ;
MOORE, PS ;
SAID, JW ;
KNOWLES, DM .
NEW ENGLAND JOURNAL OF MEDICINE, 1995, 332 (18) :1186-1191
[6]   TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90 [J].
Chen, GQ ;
Cao, P ;
Goeddel, DV .
MOLECULAR CELL, 2002, 9 (02) :401-410
[7]   Multiple sequence alignment with the Clustal series of programs [J].
Chenna, R ;
Sugawara, H ;
Koike, T ;
Lopez, R ;
Gibson, TJ ;
Higgins, DG ;
Thompson, JD .
NUCLEIC ACIDS RESEARCH, 2003, 31 (13) :3497-3500
[8]   Constitutive NF-κB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice [J].
Chugh, P ;
Matta, H ;
Schamus, S ;
Zachariah, S ;
Kumar, A ;
Richardson, JA ;
Smith, AL ;
Chaudhary, PM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (36) :12885-12890
[9]   NEMO/IKKγ:: Linking NF-κB to human disease [J].
Courtois, G ;
Smahi, A ;
Israël, A .
TRENDS IN MOLECULAR MEDICINE, 2001, 7 (10) :427-430
[10]   A fully automatic evolutionary classification of protein folds: Dali Domain Dictionary version 3 [J].
Dietmann, S ;
Park, J ;
Notredame, C ;
Heger, A ;
Lappe, M ;
Holm, L .
NUCLEIC ACIDS RESEARCH, 2001, 29 (01) :55-57