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Nucleic Acids Res. 2012 Dec;40(22):11756-68. doi: 10.1093/nar/gks933. Epub 2012 Oct 15.

AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome.

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  • 1Biomolecular NMR Laboratory, Center of Translational Genomics and Bioinformatics, Dulbecco Telethon Institute c/o S. Raffaele Scientific Institute, Milano, Italy.

Abstract

Mutations in autoimmune regulator (AIRE) gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of peripheral-tissue antigens to mediate deletional tolerance, thereby preventing self-reactivity. AIRE contains two plant homeodomains (PHDs) which are sites of pathological mutations. AIRE-PHD fingers are important for AIRE transcriptional activity and presumably play a crucial role in the formation of multimeric protein complexes at chromatin level which ultimately control immunological tolerance. As a step forward the understanding of AIRE-PHD fingers in normal and pathological conditions, we investigated their structure and used a proteomic SILAC approach to assess the impact of patient mutations targeting AIRE-PHD fingers. Importantly, both AIRE-PHD fingers are structurally independent and mutually non-interacting domains. In contrast to D297A and V301M on AIRE-PHD1, the C446G mutation on AIRE-PHD2 destroys the structural fold, thus causing aberrant AIRE localization and reduction of AIRE target genes activation. Moreover, mutations targeting AIRE-PHD1 affect the formation of a multimeric protein complex at chromatin level. Overall our results reveal the importance of AIRE-PHD domains in the interaction with chromatin-associated nuclear partners and gene regulation confirming the role of PHD fingers as versatile protein interaction hubs for multiple binding events.

PMID:
23074189
[PubMed - indexed for MEDLINE]
PMCID:
PMC3526288
Free PMC Article
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