Polypeptide Chain Collapse of Amyloidogenic Intrinsically Disordered Proteins

Abstract

My laboratory utilizes a diverse array of biophysical tools to unravel the mechanisms of protein misfolding and aggregation leading to amyloid fibril formation [1-4]. Polypeptide chain collapse of amyloidogenic intrinsically disordered proteins (IDPs) has important consequences in protein aggregation. Using a variety of prediction and spectroscopic tools, we have first established that an archetypal IDP namely κ-casein adopts a collapsed ‘pre-molten-globule’ like conformational ensemble under physiological condition [1]. Our results indicated a change in the mean hydrodynamic radius from ∼4.6 nm to ∼1.9 nm upon chain collapse. We then took the advantage of two cysteines that are separated by 77-amino acid residues and labeled them using thiol-reactive pyrene maleimide. This dual-labeled protein demonstrated a strong excimer formation upon renaturation providing a compelling evidence of polypeptide chain collapse under physiological conditions (Figure 1). I will also discuss our recent results on biologically important amyloidogenic IDPs such as α-synuclein and disordered segment of human prion protein.1. Jain et al. Biophys. J. 2011 (in press).2. Bhattacharya et al. J. Phys. Chem. B. 2011,115, 4195–4205.3. Jain et al. J.Fluoresc. 2011, 21, 615–625.4. Bhattacharya et al. J.Fluoresc. 2011, 21, 1083–1090.View Large Image | View Hi-Res Image | Download PowerPoint Slide