Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with polyribosomes.
Mutations resulting in the expansion of a polyglutamine tract in the protein ataxin-2 give rise to the neurodegenerative disorders spinocerebellar ataxia type 2 and Parkinson's disease. The normal cellular function of ataxin-2 and the mechanism by which polyglutamine expansion of ataxin-2 causes neurodegeneration are unknown. Here, we demonstrate that ataxin-2 and its Drosophila homolog, ATX2, assemble with polyribosomes and poly(A)-binding protein (PABP), a key regulator of mRNA translation. The assembly of ATX2 with polyribosomes is mediated independently by two distinct evolutionarily conserved regions of ATX2: an N-terminal Lsm/Lsm-associated domain (LsmAD), found in proteins that function in nuclear RNA processing and mRNA decay, and a PAM2 motif, found in proteins that interact physically with PABP. We further show that the PAM2 motif mediates a physical interaction of ATX2 with PABP in addition to promoting ATX2 assembly with polyribosomes. Our results suggest a model in which ATX2 binds mRNA directly through its Lsm/LsmAD domain and indirectly via binding PABP that is itself directly bound to mRNA. These findings, coupled with work on other ataxin-2 family members, suggest that ATX2 plays a direct role in translational regulation. Our results raise the possibility that polyglutamine expansions within ataxin-2 cause neurodegeneration by interfering with the translational regulation of particular mRNAs.
Satterfield
Terrence F
TF
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195-7730, USA.
Pallanck
Leo J
LJ
D000818:Animals; D000067698:Ataxin-2 / Q000378:metabolism*; D000067528:Ataxins; D002478:Cells, Cultured; D004330:Drosophila / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000209:etiology; D010455:Peptides / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism*; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism
C000622386:ATX2 protein, Drosophila; D000067698:Ataxin-2; D000067528:Ataxins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D039102:Poly(A)-Binding Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C097188:polyglutamine