Format

Send to

Choose Destination
J Biol Chem. 2018 Dec 21;293(51):19613-19623. doi: 10.1074/jbc.RA118.004808. Epub 2018 Oct 12.

The folding equilibrium of huntingtin exon 1 monomer depends on its polyglutamine tract.

Author information

1
From the Departments of Physiology and Neuroscience and.
2
the Facultad de Ciencias Básicas, Ingeniería y Tecnología, Universidad Autónoma de Tlaxcala, Calzada Apizaquito S/N, 90300 Apizaco, Tlaxcala, Mexico.
3
Biochemistry and Molecular Medicine, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033 and.
4
From the Departments of Physiology and Neuroscience and langen@usc.edu.

Abstract

Expansion of the polyglutamine (polyQ) tract in exon 1 of the huntingtin protein (Httex1) leads to Huntington's disease resulting in fatal neurodegeneration. However, it remains poorly understood how polyQ expansions alter protein structure and cause toxicity. Using CD, EPR, and NMR spectroscopy, we found here that monomeric Httex1 consists of two co-existing structural states whose ratio is determined by polyQ tract length. We observed that short Q-lengths favor a largely random-coil state, whereas long Q-lengths increase the proportion of a predominantly α-helical state. We also note that by following a mobility gradient, Httex1 α-helical conformation is restricted to the N-terminal N17 region and to the N-terminal portion of the adjoining polyQ tract. Structuring in both regions was interdependent and likely stabilized by tertiary contacts. Although little helicity was present in N17 alone, each Gln residue in Httex1 enhanced helix stability by 0.03-0.05 kcal/mol, causing a pronounced preference for the α-helical state at pathological Q-lengths. The Q-length-dependent structuring and rigidification could be mimicked in proteins with shorter Q-lengths by a decrease in temperature, indicating that lower temperatures similarly stabilize N17 and polyQ intramolecular contacts. The more rigid α-helical state of Httex1 with an expanded polyQ tract is expected to alter interactions with cellular proteins and modulate the toxic Httex1 misfolding process. We propose that the polyQ-dependent shift in the structural equilibrium may enable future therapeutic strategies that specifically target Httex1 with toxic Q-lengths.

KEYWORDS:

Huntington disease; conformational equilibrium; electron paramagnetic resonance (EPR); neurodegeneration; nuclear magnetic resonance (NMR); polyglutamine; protein misfolding

PMID:
30315108
PMCID:
PMC6314148
[Available on 2019-12-21]
DOI:
10.1074/jbc.RA118.004808
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center