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- Title
AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome.
- Authors
Gaetani, Massimiliano; Matafora, Vittoria; Saare, Mario; Spiliotopoulos, Dimitrios; Mollica, Luca; Quilici, Giacomo; Chignola, Francesca; Mannella, Valeria; Zucchelli, Chiara; Peterson, Pärt; Bachi, Angela; Musco, Giovanna
- 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.
- Publication
Nucleic acids research, 2012, Vol 40, Issue 22, p11756
- ISSN
1362-4962
- Publication type
Journal Article
- DOI
10.1093/nar/gks933