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PMID:18337722
| Citation |
Lim, J, Crespo-Barreto, J, Jafar-Nejad, P, Bowman, AB, Richman, R, Hill, DE, Orr, HT and Zoghbi, HY (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452:713-8 |
|---|---|
| Abstract |
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases. |
| Links |
PubMed PMC2377396 Online version:10.1038/nature06731 |
| Keywords |
Alleles; Animals; Ataxin-1; Ataxins; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster; Humans; Mice; Multiprotein Complexes/chemistry; Multiprotein Complexes/metabolism; Nerve Tissue Proteins/chemistry; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Nuclear Proteins/chemistry; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Open Reading Frames/genetics; Peptides/genetics; Peptides/metabolism; Protein Binding; Protein Structure, Quaternary; Purkinje Cells/cytology; Purkinje Cells/metabolism; RNA Splicing Factors; RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism; Repressor Proteins/metabolism; Ribonucleoprotein, U2 Small Nuclear/genetics; Ribonucleoprotein, U2 Small Nuclear/metabolism; Spinocerebellar Ataxias/genetics; Spinocerebellar Ataxias/metabolism; Spinocerebellar Ataxias/pathology; Trinucleotide Repeat Expansion/genetics; Two-Hybrid System Techniques |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
UniProtKB:Q96I25 |
F |
Seeded From UniProt |
complete | ||
|
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
UniProtKB:Q96RK0 |
F |
Seeded From UniProt |
complete | ||
|
MOUSE:ATX1 |
part_of |
GO:0032991: protein-containing complex |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
MOUSE:ATX1 |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
PR:Q8JZX4 |
F |
Seeded From UniProt |
complete | |
|
MOUSE:ATX1 |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
PR:Q924A2 |
F |
Seeded From UniProt |
complete | |
|
MOUSE:ATX1 |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
UniProtKB:Q924A2 |
F |
Seeded From UniProt |
complete | |
|
DROME:Q7PL81 |
involved_in |
GO:0001745: compound eye morphogenesis |
ECO:0000316: genetic interaction evidence used in manual assertion |
HGNC:10548 |
P |
Seeded From UniProt |
complete | |
|
DROME:Q7PL82 |
involved_in |
GO:0001745: compound eye morphogenesis |
ECO:0000316: genetic interaction evidence used in manual assertion |
HGNC:10548 |
P |
Seeded From UniProt |
complete | |
|
DROME:Q7PL83 |
involved_in |
GO:0001745: compound eye morphogenesis |
ECO:0000316: genetic interaction evidence used in manual assertion |
HGNC:10548 |
P |
Seeded From UniProt |
complete | |
|
MOUSE:SPF45 |
part_of |
GO:0032991: protein-containing complex |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
MOUSE:SPF45 |
located_in |
GO:0005634: nucleus |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
MOUSE:SPF45 |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
PR:P54254 |
F |
Seeded From UniProt |
complete | |
|
DROME:Q8SYI1 |
involved_in |
GO:0001745: compound eye morphogenesis |
ECO:0000316: genetic interaction evidence used in manual assertion |
HGNC:10548 |
P |
Seeded From UniProt |
complete | |
|
MOUSE:CIC |
part_of |
GO:0032991: protein-containing complex |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | ||
|
MOUSE:CIC |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
PR:P54254 |
F |
Seeded From UniProt |
complete | |
|
MOUSE:CIC |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
UniProtKB:P54254 |
F |
Seeded From UniProt |
complete | |
|
HUMAN:SPF45 |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
UniProtKB:P54253 |
F |
Seeded From UniProt |
complete | |
|
HUMAN:CIC |
enables |
GO:0005515: protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
UniProtKB:P54253 |
F |
Seeded From UniProt |
complete | |
|
enables |
GO:0042802: identical protein binding |
ECO:0000353: physical interaction evidence used in manual assertion |
UniProtKB:P54253 |
F |
Seeded From UniProt |
complete | ||
Notes
See also
References
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