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Review
. 2013:337:123-37.
doi: 10.1007/128_2012_316.

Structured crowding and its effects on enzyme catalysis

Buyong Ma  1 , Ruth Nussinov
Affiliations
Review

Structured crowding and its effects on enzyme catalysis

Buyong Ma et al. Top Curr Chem. 2013.

Abstract

Macromolecular crowding decreases the diffusion rate, shifts the equilibrium of protein-protein and protein-substrate interactions, and changes protein conformational dynamics. Collectively, these effects contribute to enzyme catalysis. Here we describe how crowding may bias the conformational change and dynamics of enzyme populations and in this way affect catalysis. Crowding effects have been studied using artificial crowding agents and in vivo-like environments. These studies revealed a correlation between protein dynamics and function in the crowded environment. We suggest that crowded environments be classified into uniform crowding and structured crowding. Uniform crowding represents random crowding conditions created by synthetic particles with a narrow size distribution. Structured crowding refers to the highly coordinated cellular environment, where proteins and other macromolecules are clustered and organized. In structured crowded environments the perturbation of protein thermal stability may be lower; however, it may still be able to modulate functions effectively and dynamically. Dynamic, allosteric enzymes could be more sensitive to cellular perturbations if their free energy landscape is flatter around the native state; on the other hand, if their free energy landscape is rougher, with high kinetic barriers separating deep minima, they could be more robust. Above all, cells are structured; and this holds both for the cytosol and for the membrane environment. The crowded environment is organized, which limits the search, and the crowders are not necessarily inert. More likely, they too transmit allosteric effects, and as such play important functional roles. Overall, structured cellular crowding may lead to higher enzyme efficiency and specificity.

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Figures

Fig. 1
Fig. 1
Allosteric proteins are sensitive to crowding effects. (a) The mini intein activity can be allosterically modulated by a loop distant from the active site. Two residues in the active site (H73 and N440) are represented by large balls and residues in the loop are represented by small balls and sticks. Three loops with different sizes were tested in [35]. Active intein has a longer loop (VR96DVE99TGE102L404). While reducing the loop length to VR96DVE99…L404 still preserved the activity, further shortening to VR96L404 inactivates the enzyme. (b) The structure of allosteric protein SARS-Co 3CL peptidase, for which the catalytic activity increases in a crowded environment. Three active site residues (H41, S144, and C145) are shown as large balls in one domain. The mutant position N214 is shown as large balls in another domain
Fig. 2
Fig. 2
Changes of the protein free energy landscape under uniform crowding and structured crowding environment. (a) The original energy landscape is represented by two conformational states α and β in a buffer solution. (b) Uniform crowding considers the effects caused by hard sphere crowding agents, which have uniform size and repulsive interactions with protein solute. This represents the strong confinement of proteins. In an environment of uniform crowding, the protein energy landscape may experience strong compression which may reflect protein folding–unfolding transition. Depending on the molecular size of the crowding agents, the relative stabilities of different conformers could increase or decrease in a uniform crowded environment. (c) Structured crowding refers to a highly coordinated cellular environment, where the overall proteome and other macromolecules pre-organized into structured clusters. In a structured crowded environment, the protein free energy landscape may be more similar to that in buffer solution. However, protein dynamics could be more sensitive than thermal stability
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