Nucleation of Huntingtin Aggregation Proceeds via Conformational Conversion of Pre-Formed, Sparsely-Populated Tetramers.

ABSTRACT: Pathogenic huntingtin exon-1 protein (htt^ex1), characterized by an expanded polyglutamine tract located between the N-terminal amphiphilic region and a C-terminal polyproline-rich domain, forms fibrils that accumulate in neuronal inclusion bodies, and is associated with a fatal, autosomal dominant neurodegenerative condition known as Huntington's disease. Here a complete kinetic model is described for aggregation/fibril formation of a htt^ex1 construct with a 35-residue polyglutamine repeat, htt^ex1Q₃₅. Using exchange NMR spectroscopy, it is previously shown that the reversible formation of a sparsely-populated tetramer of the N-terminal amphiphilic domain of htt^ex1Q₃₅, comprising a D₂ symmetric four-helix bundle, o

SUBMITTER: Torricella F 

PROVIDER: S-EPMC11199967 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature