Cellular crowding imposes global constraints on the chemistry and evolution of proteomes

Abstract

In living cells, functional protein-protein interactions compete with a much larger number of nonfunctional, or promiscuous, interactions. Several cellular properties contribute to avoiding unwanted protein interactions, including regulation of gene expression, cellular compartmentalization, and high specificity and affinity of functional interactions. Here we investigate whether other mechanisms exist that shape the sequence and structure of proteins to favor their correct assembly into functional protein complexes. To examine this question, we project evolutionary and cellular abundance information onto 397, 196, and 631 proteins of known 3D structure from Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens, respectively. On the basis of amino acid frequencies in interface patches versus the solvent-accessible protein surface, we define a propensity or "stickiness" scale for each of the 20 amino acids. We find that the propensity to interact in a nonspecific manner is inversely correlated with abundance. In other words, high abundance proteins have less sticky surfaces. We also find that stickiness constrains protein evolution, whereby residues in sticky surface patches are more conserved than those found in nonsticky patches. Finally, we find that the constraint imposed by stickiness on protein divergence is proportional to protein abundance, which provides mechanistic insights into the correlation between protein conservation and protein abundance. Overall, the avoidance of nonfunctional interactions significantly influences the physico-chemical and evolutionary properties of proteins. Remarkably, the effects observed are consistently larger in E. coli and S. cerevisiae than in H. sapiens, suggesting that promiscuous protein-protein interactions may be freer to accumulate in the human lineage.promiscuity | protein structure | interaction potential

Biophysics of protein evolution and evolutionary protein biophysics

“…This crowdedness is probably dictated by biophysical constraints imposed by a living cell's need for efficient rates of biochemical reactions [107]. Within the cellular confine, a given protein can potentially come into contact with a large number of other proteins [108,109]. Although the possibility of non-specific binding probably constitutes a biophysical constraint that might have restricted the number of proteins in a cell [110], natural proteins can function by being remarkably specific binders.…”

Searching for the Pareto frontier in multi-objective protein design

“…Notably, a similar constraint exists in natural proteomes, where complexity is limited by nonspecific interactions between proteins (Tompa and Rose 2011), and measures of protein Bstickiness^negatively correlate with expression levels (Levy et al 2012). Nearly all protein design problems are either implicitly or explicitly multiobjective, and the development of efficient algorithms for producing a Pareto optimal set of sequences is an important goal.…”

Co-evolution of proteins and solutions: protein adaptation versus cytoprotective micromolecules and their roles in marine organisms

“…This reduces diffusion, increases activity coefficients, favors inappropriate protein aggregations, and likely limits the total amount of solutes that can be packed into a cell (Levy et al, 2012). Osmolytes may help: for example, the mammalian renal osmolytes betaine, taurine and myo-inositol reduced crowding and thus formation of mRNA stress aggregates in osmotically stressed renal cells (Bounedjah et al, 2012).…”