Substrate inhibition imposes fitness penalty at high protein stability
Proteins are only moderately stable. It has long been debated whether this narrow range of stabilities is solely a result of neutral drift towards lower stability or purifying selection against excess stability is also at work - for which no experimental evidence was found so far. Here we show that mutations outside the active site in the essential E. coli enzyme adenylate kinase result in stability-dependent increase in substrate inhibition by AMP, thereby impairing overall enzyme activity at high stability. Such inhibition caused substantial fitness defects not only in the presence of excess substrate but also under physiological conditions. In the latter case, substrate inhibition caused differential accumulation of AMP in the stationary phase for the inhibition prone mutants. Further, we show that changes in flux through Adk could accurately describe the variation in fitness effects. Taken together, these data suggest that selection against substrate inhibition and hence excess stability may have resulted in a narrow range of optimal stability observed for modern proteins.
Code (0)
등록된 구현이 없습니다.
Tasks
Vocal Bursts Intensity PredictionSimilar Papers 제목 키워드 기반
Codynamic Fitness Landscapes of Coevolutionary Minimal Substrates
Coevolutionary minimal substrates are simple and abstract models that allow studying the relationships and codynamics between objective and subjective fitness. Using these models an approach is presented for defining and…
Single-molecule theory of enzymatic inhibition predicts the emergence of inhibitor-activator duality
The classical theory of enzymatic inhibition aims to quantitatively describe the effect of certain molecules -- called inhibitors -- on the progression of enzymatic reactions, but growing signs indicate that it must be r…
Statistical Mechanics of Allosteric Enzymes
The concept of allostery in which macromolecules switch between two different conformations is a central theme in biological processes ranging from gene regulation to cell signaling to enzymology. Allosteric enzymes perv…
Reaction kinetics of membrane receptors: a spatial modeling approach
The interactions between diffusing molecules and membrane-bound receptors drive numerous cellular processes. In this work, we develop a spatial model of molecular interactions with membrane receptors by homogenizing the …
Monotone but Exciting: On Evolving Monotone Boolean Functions with High Nonlinearity
Monotone Boolean functions are a structurally important class of Boolean functions, but their restricted form imposes strong limitations on achievable nonlinearity. In this paper, we investigate whether evolutionary comp…