title: Mutations in the bare lymphocyte syndrome define critical steps in the assembly of the regulatory factor X complex.
abstract: The regulatory factor X (RFX) complex, which contains RFXANK(B), RFXAP, and RFX5, binds to X and S boxes in major histocompatibility complex class II (MHC II) promoters. In the bare lymphocyte syndrome (BLS), which is a human severe combined immunodeficiency, MHC II promoters are neither occupied nor transcribed. Thus, the absence of any one subunit prevents the formation of the RFX complex. Nevertheless, except for a weak binding between RFX5 and RFXAP, no other interactions between RFX proteins have been described. In this study, we demonstrate that RFXANK(B) binds to RFXAP to form a scaffold for the assembly of the RFX complex, which then binds to DNA. Moreover, mutant RFXANK(B) and RFXAP proteins from complementation groups B and D of BLS, respectively, cannot support this interaction. Our data elucidate an intriguing medical situation, where a genetic disease targets two different surfaces that are required for the nucleation of a multisubunit DNA-protein complex.
authors.affiliation: Howard Hughes Medical Institute, Departments of Medicine, Microbiology and Immunology, University of California, San Francisco 94143-0703, USA.
authors.forename: N
authors.initials: N
authors.lastname: Nekrep
authors.forename: N
authors.initials: N
authors.lastname: Jabrane-Ferrat
authors.forename: B M
authors.initials: BM
authors.lastname: Peterlin
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D000071701:Regulatory Factor X Transcription Factors; D016511:Severe Combined Immunodeficiency / Q000097:blood* / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors