Insulin-degrading enzyme is activated by the C-terminus of α-synuclein.
The insulin-degrading enzyme (IDE) plays a key role in type-2 diabetes and typically degrades small peptides such as insulin, amyloid β and islet amyloid polypeptide. We recently reported a novel non-proteolytical interaction in vitro between IDE and the Parkinson's disease 140-residue protein α-synuclein that resulted in dual effects: arrested α-synuclein oligomers and, simultaneously, increased IDE proteolysis activity. Here we demonstrate that these outcomes arise due to IDE interactions with the C-terminus of α-synuclein. Whereas a peptide containing the first 97 residues of α-synuclein did not improve IDE activity and its aggregation was not blocked by IDE, a peptide with the C-terminal 44 residues of α-synuclein increased IDE proteolysis to the same degree as full-length α-synuclein. Because the α-synuclein C-terminus is acidic, the interaction appears to involve electrostatic attraction with IDE's basic exosite, known to be involved in activation.
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Sandeep K
SK
Sharma
Department of Chemistry, Umeå University, 90187 Umeå, Sweden.
Erik
E
Chorell
Department of Chemistry, Umeå University, 90187 Umeå, Sweden. Electronic address: pernilla.wittung@chalmers.se.
Pernilla
P
Wittung-Stafshede
D004789:Enzyme Activation; D007339:Insulysin / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
D051844:alpha-Synuclein; D007339:Insulysin
Amyloid; Insulin degrading enzyme; Parkinson's disease; Proteolysis; α-Synuclein