title: Role of the coiled-coil structural motif in polyglutamine aggregation.
abstract: Polyglutamine repeat motifs are known to induce protein aggregation in various neurodegenerative diseases, and flanking sequences can modulate this behavior. It has been proposed that the 17 N-terminal residues (Htt(NT)) of the polyglutamine-containing huntingtin protein accelerate the kinetics of aggregation due to the formation of helix-rich oligomers through helix-pairing interactions. Several hypotheses that explain the role of helical interactions in modulating aggregation have been proposed. These include (1) an increase in the effective concentration of polyglutamine chains (proximity model), (2) the induction of helical structure within the polyglutamine domain itself (transformation model), and/or (3) interdomain interactions between the flanking sequence and the polyglutamine domain (domain cross-talk model). These hypotheses are tested by studying the kinetics of polyglutamine aggregation using a Q25 sequence fused to a well-defined heterotetrameric coiled-coil model system. Using a combined spectroscopic and dye binding approach, it is shown that stable coiled-coil formation strongly inhibits polyglutamine aggregation, suggesting that the proximity and transformation models are insufficient to explain the enhanced aggregation seen in Htt(NT)-polyglutamine constructs. Consistent with other published work, our data support a model in which domain cross-talk prevents formation of a nonspecific aggregated collapsed polyglutamine state, which can act to inhibit conversion to a fibrillar state. Because our model system has a charged to nonpolar residue ratio much higher than that of the Htt(NT) sequence, domain cross-talk is severely weakened, thus favoring the nonspecific aggregation pathway and significantly inhibiting aggregation through a fibrillar pathway.
authors.affiliation: Department of Biology, Haverford College , 370 Lancaster Avenue, Haverford, Pennsylvania 19041, United States.
authors.forename: Bashkim
authors.initials: B
authors.lastname: Kokona
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Rosenthal
authors.forename: Robert
authors.initials: R
authors.lastname: Fairman
mesh_terms: D020816:Amino Acid Motifs; D006801:Humans; D000071058:Huntingtin Protein; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D066263:Protein Aggregation, Pathological
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine