Journal
BIOPHYSICAL JOURNAL
Volume 100, Issue 11, Pages 2773-2782Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2011.04.028
Keywords
-
Categories
Funding
- National Science Foundation [CBET-0852278]
- National Institutes of Health [5T32 GM-08349]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [0852278] Funding Source: National Science Foundation
Ask authors/readers for more resources
Expanded CAG diseases are progressive neurodegenerative disorders in which specific proteins have an unusually long polyglutamine stretch. Although these proteins share no other sequence or structural homologies, they all aggregate into intracellular inclusions that are believed to be pathological. We sought to determine what impact the position and number of glutamines have on the structure and aggregation of the host protein, apomyoglobin. Variable-length polyQ tracts were inserted either into the loop between the C- and D-helices (Q(n)CD) or at the N-terminus (Q(n)NT). The QnCD mutants lost some alpha-helix and gained unordered and/or beta-sheet in a length-dependent manner. These mutants were partially unfolded and rapidly assembled into soluble chain-like oligomers. In sharp contrast, the Q(n)NT mutants largely retained wild-type tertiary structure but associated into long, fibrillar aggregates. Control proteins with glycine-serine repeats (GS(8)CD and GS(8)NT) were produced. GS(8)CD exhibited similar structural perturbations and aggregation characteristics to an analogously sized Q(18)CD, indicating that the observed effects are independent of amino acid composition. In contrast to Q(18)NT, GS(8)NT did not form fibrillar aggregates. Thus, soluble oligomers are produced through structural perturbation and do not require polyQ, whereas classic fibrils arise from specific polyQ intermolecular interactions in the absence of misfolding.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available