The AXH domain adopts alternative folds the solution structure of HBP1 AXH.
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.
de Chiara
Cesira
C
National Institute for Medical Research, The Ridgeway, London, United Kingdom.
Menon
Rajesh P
RP
Adinolfi
Salvatore
S
de Boer
Jasper
J
Ktistaki
Eleni
E
Kelly
Geoff
G
Calder
Lesley
L
Kioussis
Dimitris
D
Pastore
Annalisa
A
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
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