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The rate of polyQ-mediated aggregation is dramatically affected by the number and location of surrounding domains.

Abstract：

:The nine polyglutamine (polyQ) neurodegenerative diseases are caused in part by a gain-of-function mechanism involving protein misfolding, the deposition of β-sheet-rich aggregates and neuronal toxicity. While previous experimental evidence suggests that the polyQ-induced misfolding mechanism is context dependent, the properties of the host protein, including the domain architecture and location of the polyQ tract, have not been investigated. Here, we use variants of a model polyQ-containing protein to systematically determine the effect of the location and number of flanking folded domains on polyQ-mediated aggregation. Our data indicate that when a pathological-length polyQ tract is present between two domains, it aggregates more slowly than the same-length tract in a terminal location within the protein. We also demonstrate that increasing the number of flanking domains decreases the polyQ protein's aggregation rate. Our experimental data, together with a bioinformatic analysis of all human proteins possessing polyQ tracts, suggest that repeat location and protein domain architecture affect the disease susceptibility of human polyQ proteins.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Robertson AL,Bate MA,Buckle AM,Bottomley SP

doi

10.1016/j.jmb.2011.09.014

subject

Has Abstract

pub_date

2011-11-04 00:00:00

pages

879-87

issue

4

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(11)01020-5

journal_volume

413

pub_type

杂志文章

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