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Functional interactions as a survival strategy against abnormal aggregation.

ABSTRACT: Protein aggregation is under intense scrutiny because of its role in human disease. Although increasing evidence indicates that protein native states are highly protected against aggregation, the specific protection mechanisms are poorly understood. Insight into such mechanisms can be gained through study of the relatively few proteins that aggregate under native conditions. Ataxin-3, the protein responsible for Spinocerebellar ataxia type 3, a polyglutamine expansion disease, represents one of such examples. Polyglutamine expansion is central for determining solubility and aggregation rates of ataxin-3, but these properties are profoundly modulated by its N-terminal Josephin domain. This work aims at identifying the regions that promote Josephin fibrillogenesis and rationalizing the mechanisms that protect Josephin and nonexpanded ataxin-3 from aberrant aggregation. Using different biophysical techniques, aggregation propensity predictions and rational design of amino acid substitutions, we show that Josephin has an intrinsic tendency to fibrillize under native conditions and that fibrillization is promoted by two solvent-exposed patches, which are also involved in recognition of natural substrates, such as ubiquitin. Indeed, designed mutations at these patches or substrate binding significantly reduce Josephin aggregation kinetics. Our results provide evidence that protein nonpathologic function can play an active role in preventing aberrant fibrillization and suggest the molecular mechanism whereby this occurs in ataxin-3.

SUBMITTER: Masino L

PROVIDER: S-EPMC3005437 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Functional interactions as a survival strategy against abnormal aggregation.

Masino Laura L Nicastro Giuseppe G Calder Lesley L Vendruscolo Michele M Pastore Annalisa A

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20100901 1

Protein aggregation is under intense scrutiny because of its role in human disease. Although increasing evidence indicates that protein native states are highly protected against aggregation, the specific protection mechanisms are poorly understood. Insight into such mechanisms can be gained through study of the relatively few proteins that aggregate under native conditions. Ataxin-3, the protein responsible for Spinocerebellar ataxia type 3, a polyglutamine expansion disease, represents one of ...[more]

PMID: 20810784

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Project description:Background and aimsPatients with heart failure (HF) with reduced left ventricular (LV) ejection fraction (EF) have a heterogeneous prognosis, and assessment of coronary physiology with coronary flow velocity (CFV) and coronary flow velocity reserve (CFVR) may complement established predictors based on wall motion and EF.Methods and resultsIn a prospective multicenter study design, we enrolled 1,408 HF patients (age 66 ± 12 years, 1,035 men), with EF <50%, 743 (53%) with coronary artery disease, and 665 (47%) with normal coronary arteries. Recruitment (years 2004-2022) involved 8 accredited laboratories, with inter-observer variability <10% for CFV measurement. Baseline CFV (abnormal value >31 cm/s) was obtained by pulsed-wave Doppler in mid-distal LAD. CFVR (abnormal value ≤2.0) was assessed with exercise (n = 99), dobutamine (n = 100), and vasodilator stress (dipyridamole in 1,149, adenosine in 60). Inducible myocardial ischemia was identified with wall motion score index (WMSI) stress > rest (cut-off Δ ≥ 0.12). LV contractile reserve (CR) was identified with WMSI stress < rest (cutoff Δ ≥ 0.25). Test response ranged from score 0 (EF > 30%, CFV ≥ 32 cm/s, CFVR > 2.0, LVCR present, ischemia absent) to score 5 (all steps abnormal). All-cause death was the only endpoint. Results. During a median follow-up of 990 days, 253 patients died. Independent predictors of death were EF (HR: 0.956, 95% CI: 0.943-0.968, p < 0.0001), CFV (HR: 2.407, 95% CI: 1.871-3.096, p < 0.001), CFVR (HR: 3.908, 95% CI: 2.903-5.260, p < 0.001), stress-induced ischemia (HR: 2.223, 95% CI: 1.642-3.009, p < 0.001), and LVCR (HR: 0.524, 95% CI: 0.324-.647, p = 0.008). The annual mortality rate was lowest (1.2%) in patients with a score of 0 (n = 61) and highest (31.9%) in patients with a score of 5 (n = 15, p < 0.001).ConclusionHigh resting CFV is associated with worse survival in ischemic and nonischemic HF with reduced EF. The value is independent and additive to resting EF, CFVR, LVCR, and inducible ischemia.

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Functional interactions as a survival strategy against abnormal aggregation.

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Functional interactions as a survival strategy against abnormal aggregation.

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