Poster Presentation 49th Lorne Conference on Protein Structure and Function 2024

Oxidation-induced structural transformation of p16 from monomer to amyloid is reversible by reduction of disulfide-bound dimer intermediates (#224)

Sarah G Heath 1 , Shelby G Gray 2 , Emilie M Hamzah 2 , Nicholas J Magon 1 , Vanessa K Morris 2 , Christoph Göbl 1
  1. Pathology and Biomedical Sciences, University of Otago, Christchurch, Christchurch, New Zealand
  2. School of Biology, University of Canterbury, Christchurch, New Zealand

p16 (p16INK4a) is a tumour suppressor protein responsible for controlling cell division by regulating entry into the cell cycle. We recently reported that oxidation of its cysteine residue spurs active p16 monomers to undergo structural rearrangement, forming amyloid fibrils that lack cell cycle inhibitory function1. We will present insights into the molecular mechanism of p16 oxidation, and the resulting structural transformation during amyloid formation, that were obtained using electron microscopy, solution NMR, and kinetic monitoring of fibril elongation by fluorescence assays. These techniques reveal that disulfide-linked dimers driven by oxidation are critical building blocks of the amyloid fibril, and that by reduction of disulfide bonds, amyloids disassemble and refold into their native monomer state.

  1. [1] Göbl C, Morris VK, van Dam L, Visscher M, Polderman PE, Hartlmüller C, et al. Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A. Redox Biology. 2020;28:101316.