Extended polyglutamine tracts cause aggregation and structural perturbation of an adjacent ? barrel protein

Extended polyglutamine tracts cause aggregation and structural perturbation of an adjacent ? barrel protein
Engineering Village 2
? 2006 Elsevier Inc
Accession number: 06249939864

Title: Extended polyglutamine tracts cause aggregation and structural perturbation of an adjacent ? barrel protein

Authors: Ignatova, Zoya; Gierasch, Lila M.

Author affiliation: Dept. of Biochemistry and Molecular Biology, University of Massachusetts, 913 Lederle Graduate Research Tower B, Amherst, MA 01003-9305, United States

Serial title: Journal of Biological Chemistry

Abbreviated serial title: J. Biol. Chem.

Volume: v 281

Issue: n 18

Issue date: May 5 2006

Publication year: 2006

Pages: p 12959-12967

Language: English

ISSN: 0021-9258


Document type: Journal article (JA)

Publisher: American Society for Biochemistry and Molecular Biology Inc., Bethesda, MD 20814, United States

Abstract: Formation of fibrillar intranuclear inclusions and related neuropathologies of the CAG-repeat disorders are linked to the expansion of a polyglutamine tract. Despite considerable effort, the etiology of these devastating diseases remains unclear. Although polypeptides with glutamine tracts recapitulate many of the observed characteristics of the gene products with CAG repeats, such as in vitro and in vivo aggregation and toxicity in model organisms, extended polyglutamine segments have also been reported to structurally perturb proteins into which they are inserted. Additionally, the sequence context of a polyglutamine tract has recently been shown to modulate its propensity to aggregate. These findings raise the possibility that indirect influences of the repeat tract on adjacent protein domains are contributory to pathologies. Destabilization of an adjacent domain may lead to loss of function, as well as favoring non-native structures in the neighboring domain causing them to be prone to intermolecular association and consequent aggregation. To explore these phenomena, we have used chimeras of a well studied globular protein and exon 1 of huntingtin. We find that expansion of the polyglutamine segment beyond the pathological threshold (>35 glutamines) results in structural perturbation of the neighboring protein whether the huntingtin exon is N- or C-terminal. Elongation of the polyglutamine region also substantially increases the propensity of the chimera to aggregate, both in vitro and in vivo, and in vitro aggregation kinetics of a chimera with a 53-glutamine repeat follow a nucleation polymerization mechanism with amonomeric nucleus. ? 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Number of references: 62

Ei main heading: Proteins

Ei controlled terms: Amines - Perturbation techniques - Neurology - Pathology - Disease control - Polypeptides - Toxicity - Agglomeration - Nucleation - Polymerization - Biochemistry - Molecular biology

Uncontrolled terms: Polyglutamine tracts - Barrel proteins - Polyglutamine segments - Intermolecular associations

Ei classification codes: 804.1 Organic Compounds - 921 Applied Mathematics - 461.6 Medicine - 461.7 Health Care - 815.1.1 Organic Polymers - 454.2 Environmental Impact & Protection - 802.3 Chemical Operations - 933.1.2 Crystal Growth - 815.2 Polymerization - 801.2 Biochemistry - 461.9 Biology

Treatment: Literature review (LIT); Theoretical (THR); Experimental (EXP)

DOI: 10.1074/jbc.M511523200

Database: Compendex

Compilation and indexing terms, ? 2006 Elsevier Inc. All rights reserved
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