title: The AXH domain adopts alternative folds the solution structure of HBP1 AXH.
abstract: AXH is a protein module identified in two unrelated families that comprise the transcriptional repressor HBP1 and ataxin-1 (ATX1), the protein responsible for spinocerebellar ataxia type-1 (SCA1). SCA1 is a neurodegenerative disorder associated with protein misfolding and formation of toxic intranuclear aggregates. We have solved the structure in solution of monomeric AXH from HBP1. The domain adopts a nonclassical permutation of an OB fold and binds nucleic acids, a function previously unidentified for this region of HBP1. Comparison of HBP1 AXH with the crystal structure of dimeric ATX1 AXH indicates that, despite the significant sequence homology, the two proteins have different topologies, suggesting that AXH has chameleon properties. We further demonstrate that HBP1 AXH remains monomeric, whereas the ATX1 dimer spontaneously aggregates and forms fibers. Our results describe an entirely novel, to our knowledge, example of a chameleon fold and suggest a link between these properties and the SCA1 pathogenesis.
authors.affiliation: National Institute for Medical Research, The Ridgeway, London, United Kingdom.
authors.forename: Cesira
authors.initials: C
authors.lastname: de Chiara
authors.forename: Rajesh P
authors.initials: RP
authors.lastname: Menon
authors.forename: Salvatore
authors.initials: S
authors.lastname: Adinolfi
authors.forename: Jasper
authors.initials: J
authors.lastname: de Boer
authors.forename: Eleni
authors.initials: E
authors.lastname: Ktistaki
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.forename: Lesley
authors.initials: L
authors.lastname: Calder
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kioussis
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001665:Binding Sites; D006609:High Mobility Group Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D012996:Solutions; D020754:Spinocerebellar Ataxias / Q000378:metabolism
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C486328:HBP1 protein, human; D006609:High Mobility Group Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D012996:Solutions; D012313:RNA