Fiumara F, et al. (2010) Essential role of coiled coils for aggregation and activity of Q/N-rich prions and PolyQ proteins. Cell 143(7):1121-35
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 beta 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 alpha-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.CI - Copyright (c) 2010 Elsevier Inc. All rights reserved.
|Status: Published||Type: Journal Article | Research Support, Non-U.S. Gov't||PubMed ID: 21183075|
Topics addressed in this paper
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|Non-Fungal Related Genes/Proteins|
|Protein Sequence Features|