Abstract
In a quest for finding additional structural constraints, apart from disordered segments, regulating protein half-life in the cell (and during evolution), here we recognize and assess the influence of native topology of biological proteins and their sequestration into multimeric complexes. Native topology acts as a molecular marker of protein’s mechanical resistance and consequently captures their half-life variations on genome-scale, irrespective of the enormous sequence, structural and functional diversity of the proteins. Cooperative stability (slower degradation upon sequestration into complexes) is a master regulator of oligomeric protein half-life that involves at least three mechanisms. (i) Association with multiple complexes results longer protein half-life; (ii) hierarchy of complex self-assembly involves short-living proteins binding late in the assembly order and (iii) binding with larger buried surface area leads to slower subunit dissociation and thereby longer half-life. Altered half-lives of paralog proteins refer to their structural divergence and oligomerization with non-identical set of complexes.
