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Autoimmune Regulator Protein

The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform

Giovanna Musco – 1st expert on this subject based on the ideXlab platform

  • Exploring PHD Fingers and H3K4me0 Interactions with Molecular Dynamics Simulations and Binding Free Energy Calculations: AIRE-PHD1, a Comparative Study
    PLOS ONE, 2012
    Co-Authors: Dimitrios Spiliotopoulos, Andrea Spitaleri, Giovanna Musco

    Abstract:

    PHD fingers represent one of the largest families of epigenetic readers capable of decoding post-translationally modified or unmodified histone H3 tails. Because of their direct involvement in human pathologies they are increasingly considered as a potential therapeutic target. Several PHD/histone-peptide structures have been determined, however relatively little information is available on their dynamics. Studies aiming to characterize the dynamic and energetic determinants driving histone peptide recognition by epigenetic readers would strongly benefit from computational studies. Herein we focus on the dynamic and energetic characterization of the PHD finger subclass specialized in the recognition of histone H3 peptides unmodified in position K4 (H3K4me0). As a case study we focused on the first PHD finger of Autoimmune Regulator Protein (AIRE-PHD1) in complex with H3K4me0. PCA analysis of the covariance matrix of free AIRE-PHD1 highlights the presence of a “flapping” movement, which is blocked in an open conformation upon binding to H3K4me0. Moreover, binding free energy calculations obtained through Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) methodology are in good qualitative agreement with experiments and allow dissection of the energetic terms associated with native and alanine mutants of AIRE-PHD1/H3K4me0 complexes. MM/PBSA calculations have also been applied to the energetic analysis of other PHD fingers recognizing H3K4me0. In this case we observe excellent correlation between computed and experimental binding free energies. Overall calculations show that H3K4me0 recognition by PHD fingers relies on compensation of the electrostatic and polar solvation energy terms and is stabilized by non-polar interactions.

  • nmr structure of the first phd finger of Autoimmune Regulator Protein aire1 insights into Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy apeced disease
    Journal of Biological Chemistry, 2005
    Co-Authors: M J Bottomley, Gunter Stier, Danilo Pennacchini, Gaelle Legube, B Simon, Asifa Akhtar, Michael Sattler, Giovanna Musco

    Abstract:

    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.

M J Bottomley – 2nd expert on this subject based on the ideXlab platform

  • nmr structure of the first phd finger of Autoimmune Regulator Protein aire1 insights into Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy apeced disease
    Journal of Biological Chemistry, 2005
    Co-Authors: M J Bottomley, Gunter Stier, Danilo Pennacchini, Gaelle Legube, B Simon, Asifa Akhtar, Michael Sattler, Giovanna Musco

    Abstract:

    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.

Caterina Cancrini – 3rd expert on this subject based on the ideXlab platform

  • the possible implication of the s250c variant of the Autoimmune Regulator Protein in a patient with autoimmunity and immunodeficiency in silico analysis suggests a molecular pathogenic mechanism for the variant
    Gene, 2014
    Co-Authors: Emanuele Bellacchio, Alessia Palma, Stefania Corrente, Francesco Di Girolamo, Helen E Kemp, Gigliola Di Matteo, Laura Comelli, Rita Carsetti, Simona Cascioli, Caterina Cancrini

    Abstract:

    Abstract Autoimmunity can develop from an often undetermined interplay of genetic and environmental factors. Rare forms of Autoimmune conditions may also result from single gene mutations as for Autoimmune polyendocrinopathy-candidiasis–ectodermal dystrophy, an autosomal recessive disease associated with mutated forms of the Autoimmune Regulator gene. It was proposed that genetic variability in the Autoimmune Regulator locus, in particular heterozygous loss-of-function mutations, might favor the development of organ-specific autoimmunity by affecting the presentation of self-antigens in the thymus. Indeed, heterozygous mutations of the Autoimmune Regulator gene were reported in patients with organ-specific autoimmunity. Also, in primary immunodeficiencies, a breakdown in central/peripheral tolerance frequently produces association with autoimmunity. The causative link may involve a common genetic background and several gene defects have been identified as putative culprits. We report a unique patient, a 14 year old male from Lazio region, affected by common variable immunodeficiency associated with Autoimmune manifestations (alopecia, onychodystrophy) and heterozygote for the S250C variant located in the SAND domain of the Autoimmune Regulator gene Protein. To our knowledge this is the first report of the S250C variant in a patient bearing this unusual combination of autoimmunity and immunodeficiency. To obtain insights into the possible molecular effects of the S250C variant, we have carried out an in silico analysis of the SAND domain structure of the Autoimmune Regulator Protein. In particular, homology modeling has allowed us to observe that the cysteine introduced by the S250C variant is surrounded by cationic residues, and by means of molecular dynamics simulations together with pK a calculations, we have shown that these residues remain stably proximal to cysteine-250 lowering its pK a and thus conferring high chemical reactivity to the mutated residue. We propose that the enhanced reactivity of cysteine-250, which is likely to impair the Protein function but probably insufficient to produce alone a phenotype as a heterozygous S250C variant due to compensation mechanisms, might become manifest when combined with other genetic/environmental factors. These results can provide the rationale for the patient’s unusual phenotype, shedding new light into the pathogenesis of the clinical association of autoimmunity and immunodeficiency.