Polyglutamine Solution-State Structural Propensity Is Repeat Length Dependent

Abstract

Expanded polyglutamine (polyQ) tracts in protein, which are known to induce their aggregation, are associated with numerous neurodegenerative diseases. Longer polyQ tracts correlate with faster protein aggregation kinetics and a decreased age of onset for polyQ disease symptoms. Here, we use UV resonance Raman spectroscopy, circular dichroism spectroscopy, and metadynamics simulations to investigate the solution-state structures of the D 2 Q 15 K 2 (Q15) and D 2 Q 20 K 2 (Q20) peptides. Using metadynamics, we explore the conformational energy landscapes of Q15 and Q20 and investigate the relative energies and activation barriers between these lowenergy structures. We compare the solution-state structures of D 2 Q 10 K 2 (Q10), Q15, and Q20 to determine the dependence of polyQ structure on the Q tract length. We show that these peptides can adopt two distinct monomeric conformations: an aggregation-resistant PPII-like conformation and an aggregation-prone β-strand-like conformation. We find that longer polyQ peptides have an increased preference for the aggregation-prone β-strand-like conformation. This preference may play an important role in the increased aggregation rate of longer polyQ peptides that are thought to lead to decreased neurodegenerative disease age of onset for polyQ disease patients.

Mechanisms by Which Organic Solvent Exchange Transforms Responsive Pure Protein Hydrogels into Responsive Organogels

“…The secondary structures of BSA hydrogels, organogels, and water incubated organogels were investigated using UV Resonance Raman (UVRR) spectroscopy. UVRR spectroscopy is a powerful tool for investigating the hydrogen bonding, , solvation environment, , and secondary structure ,, in proteins. , UVRR measurements were performed with an excitation wavelength of ∼204 nm that is in resonance with the secondary amide π → π* transitions of the polypeptide backbone . This enhances the Raman scattering of vibrations that couple to the backbone amide electronic transitions …”

A Model for Inhomogeneously Broadened Raman Bands

“…10,11,16 This method of modeling inhomogeneous Raman bands has been used extensively. 11,17,18 The frequency domain analysis of bandwidths is more limited compared to that of the time domain because it provides less information, relies on estimations of the homogeneous linewidth, and separates all fluctuations into two components (fast and slow). However, because this model can be used to analyze a frequency domain Raman spectrum, it can be widely used.…”

Stabilization of elongated polyglutamine tracts by a helical peptide derived from N‐terminal huntingtin

“…The outcome of addition of a single glutamine residue to the normal length to the age of disease onset when the length of the mutant stretch was 40–50Q was significantly higher than when the mutant protein harboured a polyQ stretch above 60Q 13 . Even in the benign region, the monomer adopts an increasingly aggregation‐prone conformation with increase in polyQ length 14 . PolyQ length may not be the sole determinant of progression of some disease parameters like weight loss and motor, cognitive and functional loss 15 .…”

“…13 Even in the benign region, the monomer adopts an increasingly aggregation-prone conformation with increase in polyQ length. 14 PolyQ length may not be the sole determinant of progression of some disease parameters like weight loss and motor, cognitive and functional loss. 15 One probable role of huntingtin is in neuronal survival 16 and co-aggregation of benign and mutant huntingtin may be the cause of a more visible "loss of function" in the case of shorter polyQ tracts of the mutant protein.…”