Effects of detergent on α‐synuclein structure. A native ms‐ion mobility study

Abstract

The intrinsically disordered protein α‐synuclein plays a major role in Parkinson’s disease. The protein can oligomerize resulting in the formation of various aggregated species in neuronal cells, leading to neurodegeneration. The interaction of α‐synuclein with biological cell membranes plays an important role for specific functions of α‐synuclein monomers, e.g., in neurotransmitter release. Using different types of detergents to mimic lipid molecules present in biological membranes, including the presence of Ca2+ ions as an important structural factor, we aimed to gain an understanding of how α‐synuclein interacts with membrane models and how this affects the protein conformation and potential oligomerization. We investigated detergent binding stoichiometry, affinity and conformational changes of α‐synuclein taking detergent concentration, different detergent structures and charges into account. With native nano‐electrospray ionization ion mobility‐mass spectrometry, we were able to detect unique conformational patterns resulting from binding of specific detergents to α‐synuclein. Our data demonstrate that α‐synuclein monomers can interact with detergent molecules irrespective of their charge, that protein‐micelle interactions occur and that micelle properties are an important factor.