Poster Presentation The 42nd Lorne Conference on Protein Structure and Function 2017

Surveillance of the mechanisms controlling proteome foldedness with a focus on organelles and aging (#225)

Candice Raeburn 1 , Rebecca Wood 1 , Alex Dickson 2 , Hannah Nicholas 3 , Gawain McColl 4 , Danny Hatters 1
  1. Bio21, Melbourne, VIC, Australia
  2. Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan , USA
  3. School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia
  4. Neurodegeneration division, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia

Proteostasis (protein homeostasis) is essential for keeping the proteome functional. This process controls protein synthesis, folding and degradation and involves hundreds of genes, including those encoding chaperones, to form extensive quality control (QC) networks1. Imbalances in proteostasis are implicated in a range of aggregation-based neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Huntington’s and Alzheimer’s diseases2,3. Currently there is a lack of capacity to quantitatively measure proteostasis imbalance and therefore we are limited in understanding how proteostasis imbalance manifests during disease. We have generated a new biosensor system to address this shortfall. The biosensor is a genetically encoded unfolded “bait” flanked by two fluorescent proteins to assay foldedness by fluorescence resonance energy transfer. Proteostasis efficiency is reported by measurement of the efficiency to which the bait interacts with the QC. We report here how this biosensor works and ongoing projects to focus the biosensor into discrete intracellular locations and in a nematode whole animal model for probing organismal and aging-related changes in proteostasis.

 

  1. Kim, Y. E., Hipp, M. S., Bracher, A., Hayer-Hartl, M. & Ulrich Hartl, F. Molecular Chaperone Functions in Protein Folding and Proteostasis. Annu. Rev. Biochem. 82, 323–355 (2013).
  2. Morimoto, R. I. & Cuervo, A. M. Proteostasis and the Aging Proteome in Health and Disease. Journals Gerontol. Ser. A Biol. Sci. Med. Sci. 69, S33–S38 (2014).
  3. Vilchez, D., Saez, I. & Dillin, A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 5, 5659 (2014).