Abrogation of prenucleation, transient oligomerization of the Huntingtin exon 1 protein by human profilin I

Proceedings of the National Academy of Sciences of the United States of America
Alberto CecconG Marius Clore

Abstract

Human profilin I reduces aggregation and concomitant toxicity of the polyglutamine-containing N-terminal region of the huntingtin protein encoded by exon 1 (httex1) and responsible for Huntington's disease. Here, we investigate the interaction of profilin with httex1 using NMR techniques designed to quantitatively analyze the kinetics and equilibria of chemical exchange at atomic resolution, including relaxation dispersion, exchange-induced shifts, and lifetime line broadening. We first show that the presence of two polyproline tracts in httex1, absent from a shorter huntingtin variant studied previously, modulates the kinetics of the transient branched oligomerization pathway that precedes nucleation, resulting in an increase in the populations of the on-pathway helical coiled-coil dimeric and tetrameric species (τex ≤ 50 to 70 μs), while leaving the population of the off-pathway (nonproductive) dimeric species largely unaffected (τex ∼750 μs). Next, we show that the affinity of a single molecule of profilin to the polyproline tracts is in the micromolar range (Kdiss ∼ 17 and ∼ 31 μM), but binding of a second molecule of profilin is negatively cooperative, with the affinity reduced ∼11-fold. The lifetime of a 1:1 complex of ht...Continue Reading

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Citations

Mar 2, 2021·Chembiochem : a European Journal of Chemical Biology·Marielle A WältiG Marius Clore
May 6, 2021·Current Opinion in Structural Biology·H Jane Dyson, Peter E Wright
Jul 3, 2021·International Journal of Molecular Sciences·Arnaud MarquetteBurkhard Bechinger
Aug 31, 2021·Frontiers in Cell and Developmental Biology·Kai MurkJuliane Schiweck
Nov 2, 2021·Frontiers in Molecular Neuroscience·Maria Lucia PigazziniJanine Kirstein

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