[Research] 2020/06/15

How are functionally important residues regulated by the protein local environment?

Researchers Karine Mazmanian and Karen Sargsyan led by Carmay Lim, Distinguished Research Fellow at the Institute of Biomedical Sciences, have explored this question in a recent Perspective in the Journal of the American Chemical Society. They formulate three key physicochemical factors for regulating a protein’s functional site and illustrate how these factors are applied to regulate the functions of free/metal-bound Cys in proteins.



How the Local Environment of Functional Sites Regulates Protein Function



Tight regulation mechanisms are needed for proteins to perform their targeted biological functions and ensure well-orchestrated response to various external and internal events in the cell. Functional residues/sites are well-studied, but their regulation by the local environment remains unclear. In this Perspective, we introduce the concept of molecular regulation by the protein, which provides an optimal local environment around the functional site.

Previous studies are limited to identifying ways of fine-tuning the target functional sites in certain proteins or protein classes/families. Hence, the key physicochemical principles underlying the formation of the local environments around functional sites in proteins remain elusive. How the best local environment of functionally important residues is selected against the far larger number of non-functional conformations remains enigmatic.


Questions addressed

In this Perspective, we attempt to answer the following questions:

1.   What strategies do proteins employ to regulate the activities of their functional sites?

2.   What are the main physicochemical factors that regulate a functional site’s activity?

3.   In the case of functional Cys, which of these factors contributes most to their regulation?



1.   We distill three intertwined physicochemical factors that regulate the functional site at the molecular level; viz., (i) its immediate interactions, (ii) its solvent accessibility, and (iii) its conformational flexibility.

2.   We show how proteins employ these key principles to organize the local environment around functional Cys residues and how this environment regulates the reactivity of Zn-bound Cys/ H2O, metal ion toxicity and release, as well as the role of atypical Zn-sites.



Functional sites are entities embedded in an optimal local environment that is regulated by the protein. Our proposed physicochemical principles governing formation of optimal local environments around the functional sites would help to elucidate how the protein matrix controls the metal-binding site and guide the design of functional metalloproteins, enzymes, and biosensors or rational drug design. Studying the local environments of protein sites improves not only our understanding of how protein function is regulated on the molecular level but also our ability to modulate regulation of therapeutically important proteins. 


How the Local Environment of Functional Sites Regulates Protein Function

Karine Mazmanian, Karen Sargsyan, and Carmay Lim

J. Am. Chem. Soc. 2020

Article link