Spontaneous protein backbone rearrangements: Molecular wear-and-tear vs beneficial maturation.

15^th May 2025, 14:00
Manuel Muller
King's College London, UK

Abstract

Within their lifetimes, proteins are subject to spontaneous modifications of their backbones. Typically considered as molecular wear-and-tear, this process involves the rearrangement of Asn and Asp residues to their beta-linked isomer, isoaspartate (isoAsp). This modification is thought to contribute to ageing and various associated pathologies including neurodegenerative diseases. However, the molecular consequences of isoAsp formation on protein function are poorly understood. I will briefly present our recent work that leverages protein semisynthesis to generate precisely ‘aged’ histones, revealing a surprising robustness of chromatin against molecular wear-and-tear [1]. Conversely, we have shown that isoAsp can also be a beneficial protein ‘maturation’ process, exemplified by the essential bacterial enzyme and antibiotic target MurA, which is stabilised by an isoAsp residue [2]. These works demonstrate how nature not only protects its proteins from negative consequences of molecular wear-and-tear but directly exploits the underlying chemical processes to access unusual structural motifs.
[1] T Zhang, LF Guerra, Y Berlina, JR Wilson, B Fierz, and MM Müller. (2025) Semisynthesis of Isomerized Histone H4 Reveals Robustness and Vulnerability of Chromatin toward Molecular Aging, J Amer Chem Soc 147, 4952.
[2] T Zhang, K Hansen, A Politis, and MM Müller. (2020) An Unusually Rapid Protein Backbone Modification Stabilizes the Essential Bacterial Enzyme MurA, Biochemistry 59, 3683.