HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 12, 11505-11512, March 25, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/12/11505    most recent M413959200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bottomley, M. J. Articles by Musco, G. Search for Related Content PubMed PubMed Citation Articles by Bottomley, M. J. Articles by Musco, G. Social Bookmarking                      What's this?

NMR Structure of the First PHD Finger of Autoimmune Regulator Protein (AIRE1)

INSIGHTS INTO AUTOIMMUNE POLYENDOCRINOPATHY-CANDIDIASIS-ECTODERMAL DYSTROPHY (APECED) DISEASE^*

Matthew James Bottomley, Gunter Stier, Danilo Pennacchini¶, Gaelle Legube, Bernd Simon, Asifa Akhtar, Michael Sattler, and Giovanna Musco¶||

From the Istituto di Ricerche di Biologia Molecolare P. Angeletti, Via Pontina Km. 30.600, 00040 Pomezia (RM), Italy, the European Molecular Biology Laboratory, Meyerhofstrasse1, 69117 Heidelberg, Germany, and the ^¶Biomolecular NMR Laboratory, Dulbecco Telethon Institute c/o S. Raffaele Scientific Institute, Via Olgettina 58, 20132, Milano, Italy

Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal recessively inherited disease: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers. The first PHD finger of AIRE1 is a mutational hot spot, to which several pathological point mutations have been mapped. Using heteronuclear NMR spectroscopy, we determined the solution structure of the first PHD finger of AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the domain. We performed a conformational analysis of pathological AIRE1-PHD1 mutants that allowed us to rationalize the structural impact of APECED-causing mutations and to identify an interaction site with putative protein ligands of the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD finger fold, with a highly conserved tryptophan buried inside the structure. The PHD finger is stabilized by two zinc ions coordinated in an interleaved (cross-brace) scheme. This zinc coordination resembles RING finger domains, which can function as E3 ligases in the ubiquitination pathway. Based on this fold similarity, it has been suggested that PHD fingers might also function as E3 ligases, although this hypothesis is controversial. At variance to a previous report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3 ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1 and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure is clearly distinct from the RING finger fold. Our results point to a function of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in some APECED mutations.

Received for publication, December 13, 2004 , and in revised form, January 12, 2005.

The atomic coordinates (code 1XWH) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

Chemical shift and restraints lists that were used in the structure calculations (code 6374) have been deposited in the BioMagResBank.

^* This work was supported in part by EMBO short-term (ASTF1442002) and long-term (ALTF 372-2003) fellowships, respectively (to G. M. and G. L.), Dr. R. Bazzo, the Istituto di Ricerche di Biologia Molecolare, the Consorzio Interuniversitario Risonanze Magnetiche di Metalloproteine Paramagnetiche (University of Florence, Italy) (to M. J. B.), and the Deutsche Forschungsgesellschaft (to M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Materials.

^|| To whom correspondence should be addressed. Tel.: 390226434824; Fax: 390226434153; E-mail: musco.giovanna{at}hsr.it or gmusco{at}dti.telethon.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				F. Chignola, M. Gaetani, A. Rebane, T. Org, L. Mollica, C. Zucchelli, A. Spitaleri, V. Mannella, P. Peterson, and G. Musco The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation Nucleic Acids Res., May 1, 2009; 37(9): 2951 - 2961. [Abstract] [Full Text] [PDF]

				A. S. Koh, A. J. Kuo, S. Y. Park, P. Cheung, J. Abramson, D. Bua, D. Carney, S. E. Shoelson, O. Gozani, R. E. Kingston, et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity PNAS, October 14, 2008; 105(41): 15878 - 15883. [Abstract] [Full Text] [PDF]

				M. Karbowski, A. Neutzner, and R. J. Youle The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division J. Cell Biol., October 3, 2007; 178(1): 71 - 84. [Abstract] [Full Text] [PDF]

				B. E. Dul and N. C. Walworth The Plant Homeodomain Fingers of Fission Yeast Msc1 Exhibit E3 Ubiquitin Ligase Activity J. Biol. Chem., June 22, 2007; 282(25): 18397 - 18406. [Abstract] [Full Text] [PDF]

				I. Gavanescu, B. Kessler, H. Ploegh, C. Benoist, and D. Mathis Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity PNAS, March 13, 2007; 104(11): 4583 - 4587. [Abstract] [Full Text] [PDF]

				E. Kekalainen, H. Tuovinen, J. Joensuu, M. Gylling, R. Franssila, N. Pontynen, K. Talvensaari, J. Perheentupa, A. Miettinen, and T. P. Arstila A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy J. Immunol., January 15, 2007; 178(2): 1208 - 1215. [Abstract] [Full Text] [PDF]