Conformation Polymorphism of Polyglutamine Proteins

Structural basis of the cytotoxicity of soluble polyQ proteins is the key to understanding polyQ disease mechanisms. The ‘linear lattice’ model and the ‘conformation emergence’ model provide distinct explanations of the conformation–cytotoxicity relationship of polyQ proteins. The conformation ‘polymorphism’ of polyQ proteins is a key to reveal the conformation–cytotoxicity relationship of polyQ proteins. Recent studies on protein degradation rates of different mHTT species recognized by different polyQ antibodies provide strong evidence demonstrating the polyQ ‘polymorphism’. Future studies of polyQ protein interactomes and post-translational modifications as well as polyQ protein–polyQ antibody complex structures may provide additional evidence demonstrating the polyQ ‘polymorphism’. Expanded polyglutamine (polyQ) stretches within endogenous proteins cause at least nine human diseases. The structural basis of polyQ pathogenesis is the key to understanding fundamental mechanisms of these diseases, but it remains unclear and controversial due to a lack of polyQ protein structures at the single-atom level. Various hypotheses have been proposed to explain the structure–cytotoxicity relationship of pathogenic proteins with polyQ expansion, largely based on indirect evidence. Here we review these hypotheses and their supporting evidence, along with additional insights from recent structural biology and chemical biology studies, with a focus on Huntingtin (HTT), the most extensively studied polyQ disease protein. Lastly, we propose potential novel strategies that may further clarify the conformation–cytotoxicity relationship of polyQ proteins. Expanded polyglutamine (polyQ) stretches within endogenous proteins cause at least nine human diseases. The structural basis of polyQ pathogenesis is the key to understanding fundamental mechanisms of these diseases, but it remains unclear and controversial due to a lack of polyQ protein structures at the single-atom level. Various hypotheses have been proposed to explain the structure–cytotoxicity relationship of pathogenic proteins with polyQ expansion, largely based on indirect evidence. Here we review these hypotheses and their supporting evidence, along with additional insights from recent structural biology and chemical biology studies, with a focus on Huntingtin (HTT), the most extensively studied polyQ disease protein. Lastly, we propose potential novel strategies that may further clarify the conformation–cytotoxicity relationship of polyQ proteins. dichroism involving circularly polarized light. Since the spectra of these molecules in the far ultraviolet (UV) regions are dominated by certain transitions of amide groups and geometries of the polypeptide backbones, their spectra are reflective of the different types of secondary structures present. Consequently, analyses can provide information on the overall structure of that protein. an assay for protein degradation measurements based on Click chemistry and Homogeneous Time Resolved Fluorescence (HTRF) technologies. a correlation analysis of fluctuation of the fluorescence intensity. Its applications include analysis of the concentration fluctuations of fluorescent particles (molecules) in solution or in intact living cells. the fibrillar mHTT aggregates appear to lack a defined shape and is composed of fibres organized in an astral morphology. They do not exchange protein with the soluble phase. The globular aggregates are spherically shaped with discrete and well-defined edges. They are loosely packed and can readily exchange with the soluble phase. a stochastic model describing a sequence of possible events in which the probability of each event depends only on the state attained in the previous event. a physical phenomenon in which nuclei in a magnetic field absorb and re-emit electromagnetic radiation. NMR spectroscopy is one of the principal techniques used to obtain physical, chemical, electronic and structural information about molecules. the ability to exist in several different forms. In this review, we propose that the polyQ proteins may exhibit polymorphism at the conformation level. polyglutamine (PolyQ)-related diseases are dominant late-onset genetic disorders that are manifested by progressive neurodegeneration, encompassing Huntington disease (HD), spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and the spinocerebellar ataxias SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17. the covalent and generally enzyme-mediated modification of proteins during or after protein biosynthesis. Phosphorylation, glycosylation, ubiquitination, S-nitrosylation, methylation, N-acetylation, and lipidation are among the common PTMs. a polymer conformation where the monomer subunits are oriented randomly while still being bonded to adjacent units. a biophysical technique used to measure distances at the 1–10 nanometer scale in single molecules, typically biomolecules. a tool used for identifying the atomic and molecular structure of a crystal, in which the crystalline atoms cause a beam of incident X-rays to diffract into many specific directions.