Invited Speaker 23rd International Society of Magnetic Resonance Conference 2023

Redox-regulated amyloid fibril formation of the tumour suppressor p16 (#76)

Sarah Heath 1 , Christoph Goebl 1 , Vanessa Morris 2
  1. Centre for Free Radical Research, Department of Pathology, University of Otago, Christchurch, Canterbury, New Zealand
  2. School of Biological Sciences, University of Canterbury, Christchurch, New Zealand

p16INK4A (p16) is a critical regulator of the mammalian cell-cycle that is found to be mutated in many cancers. Accumulation of p16 leads to senescence and is a molecular marker of cellular ageing. We have found that under oxidizing conditions, the single cysteine residue of p16 forms an intermolecular disulfide bond. Formation of the disulfide-linked dimer leads to a dramatic structural rearrangement of the protein, from an all alpha-helical structure, to beta‑sheet amyloid fibrils.1 Conversion to amyloid fibril structures prevents p16 from carrying out its normal function as a kinase inhibitor, and therefore p16 amyloid formation may be a novel regulatory mechanism of p16 activity. We are currently investigating the structure and formation mechanism of p16 amyloid fibrils, using liquid and solid-state NMR, fluorescence assays and mass spectrometry. We are also investigating how cancer-associated mutations may alter p16 amyloid formation. These findings will give insight into a novel disulfide-linked amyloid structure, as well as highlighting their potential role in cancer and cell division mechanisms.

  1. Göbl C.1, Morris, V.K. 1, van Dam, L., Visscher M., Polderman P., Hartlmüller C., de Ruiter H., Hora, M., Birner-Gruenberge, R., Vos H., Reif, B., Madl T. and T. Dansen. (2020) Cysteine oxidation triggers amyloid fibril formation of the tumor suppressor p16INK4A. Redox Biology 28, 101216