Essential role of coiled coils for aggregation and activity of Q/N-rich prions and PolyQ proteins.
Cell
; 143(7): 1121-35, 2010 Dec 23.
Article
in En
| MEDLINE
| ID: mdl-21183075
ABSTRACT
The functional switch of glutamine/asparagine (Q/N)-rich prions and the neurotoxicity of polyQ-expanded proteins involve complex aggregation-prone structural transitions, commonly presumed to be forming ß sheets. By analyzing sequences of interaction partners of these proteins, we discovered a recurrent presence of coiled-coil domains both in the partners and in segments that flank or overlap Q/N-rich and polyQ domains. Since coiled coils can mediate protein interactions and multimerization, we studied their possible involvement in Q/N-rich and polyQ aggregations. Using circular dichroism and chemical crosslinking, we found that Q/N-rich and polyQ peptides form α-helical coiled coils in vitro and assemble into multimers. Using structure-guided mutagenesis, we found that coiled-coil domains modulate in vivo properties of two Q/N-rich prions and polyQ-expanded huntingtin. Mutations that disrupt coiled coils impair aggregation and activity, whereas mutations that enhance coiled-coil propensity promote aggregation. These findings support a coiled-coil model for the functional switch of Q/N-rich prions and for the pathogenesis of polyQ-expansion diseases.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Aplysia
/
Prions
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell
Year:
2010
Type:
Article
Affiliation country:
United States