Biological roles of proteome homochirality maintenance and the underlying mechanisms
Description: Homochirality is a fundamental principle of life. Accordingly, biomolecules occur in only one chiral form, L-amino-acids in proteins and D-sugars in DNA/RNA. While D-amino acids are thought to be non-proteinogenic, recent advances demonstrate that proteins can undergo spontaneous chiral post-translational modifications under conditions of stress and aging. Despite its pivotal importance, the underlying mechanisms controlling homochirality are unknown, as are the biological consequences of homochirality loss. We have shown, for the first time, a direct link between D-amino acids and protein dysfunction in vivo, which in turn promotes a progressive ‘heterochirality syndrome’, through a cascading effect across biological scales spanning from molecular homochirality loss to resistance to caspase activity, increased tumour susceptibility and shortened lifespan. The goal is to gain an understanding of the underlying mechanisms connecting heterochirality to biological sequelae, using novel interdisciplinary approaches. We aim to identify heterochiral caspase targets that link impaired caspase activity to heterochirality syndromes, and new putative hot spot sequences in proteins with high susceptibility to epimerisation. This will help us explore new cellular processes that are affected by heterochirality. Our last objective is combining chiral-selective tools and genetic screening to identify unknown chirality-regulating genes that preserve homochirality. Our integrative approach will provide fresh insights into how homochirality is maintained in live organisms and what are the pathophysiological outcomes of the deviation from homochirality. Knowledge gained from our work will also help answering open questions related to cell biology and physiology, that have yet to be linked to homochirality loss.
Funder: Agence Nationale de la Recherche
Amount: €376,800
Funding type: research
Funder scheme: AAPG2024
Start date: 2024-11-01
Investigator: Agnes BANRETI
Institution: Institut de Biologie Valrose
Subfield: Biochemistry
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: ANR-24-CE14-2361
OpenAlex ID: G947717356