The 17-residue-long N terminus in huntingtin controls stepwise aggregation in solution and on membranes via different mechanisms.

ABSTRACT: Aggregation of huntingtin protein arising from expanded polyglutamine (polyQ) sequences in the exon-1 region of mutant huntingtin plays a central role in the pathogenesis of Huntington's disease. The huntingtin aggregation pathways are of therapeutic and diagnostic interest, but obtaining critical information from the physiologically relevant htt exon-1 (Httex1) protein has been challenging. Using biophysical techniques and an expression and purification protocol that generates clean, monomeric Httex1, we identified and mapped three distinct aggregation pathways: 1) unseeded in solution; 2) seeded in solution; and 3) membrane-mediated. In solution, aggregation proceeded in a highly stepwise manner, in which the individual domains (N terminus containing 17 amino acids (N17), polyQ, and prol

SUBMITTER: Pandey NK 

PROVIDER: S-EPMC5818184 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature