SUMO1 hinders α‐Synuclein fibrillation by inducing structural compaction

Abstract

AbstractSmall Ubiquitin‐like Modifier 1 (SUMO1) is an essential protein for many cellular functions, including regulation, signaling, etc., achieved by a process known as SUMOylation, which involves covalent attachment of SUMO1 to target proteins. SUMO1 also regulates the function of several proteins via non‐covalent interactions involving the hydrophobic patch in the target protein identified as SUMO Binding or Interacting Motif (SBM/SIM). Here, we demonstrate a crucial functional potential of SUMO1 mediated by its non‐covalent interactions with α‐Synuclein, a protein responsible for many neurodegenerative diseases called α‐Synucleinopathies. SUMO1 hinders the fibrillation of α‐Synuclein, an intrinsically disordered protein (IDP) that undergoes a transition to β‐structures during the fibrillation process. Using a plethora of biophysical techniques, we show that SUMO1 transiently binds to the N‐terminus region of α‐Synuclein non‐covalently and causes structural compaction, which hinders the self‐association process and thereby delays the fibrillation process. On the one hand, this study demonstrates an essential functional role of SUMO1 protein concerning neurodegeneration; it also illustrates the commonly stated mechanism that IDPs carry out multiple functions by structural adaptation to suit specific target proteins, on the other. Residue‐level details about the SUMO1‐α‐Synuclein interaction obtained here also serve as a reliable approach for investigating the detailed mechanisms of IDP functions.