Regulation of MIF Enzymatic Activity by an Allosteric Site at the Central Solvent Channel

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2020 May 21

PMID 32433911

Citations 10

Authors

Georgios Pantouris

Leepakshi Khurana

Anthony Ma

Erin Skeens

Krystle Reiss

Victor S Batista

George P Lisi

Elias J Lolis

Affiliations

Soon will be listed here.

Abstract

In proteins with multiple functions, such as macrophage migration inhibitory factor (MIF), the study of its intramolecular dynamic network can offer a unique opportunity to understand how a single protein is able to carry out several nonoverlapping functions. A dynamic mechanism that controls the MIF-induced activation of CD74 was recently discovered. In this study, the regulation of tautomerase activity was explored. The catalytic base Pro1 is found to form dynamic communications with the same allosteric node that regulates CD74 activation. Signal transmission between the allosteric and catalytic sites take place through intramolecular aromatic interactions and a hydrogen bond network that involves residues and water molecules of the MIF solvent channel. Once thought to be a consequence of trimerization, a regulatory function for the solvent channel is now defined. These results provide mechanistic insights into the regulation of catalytic activity and the role of solvent channel water molecules in MIF catalysis.

Citing Articles

Conformational Flexibility of the C-Terminal Region Influences Distal Active Site Residues Across the Tautomerase Superfamily.

Argueta C, Parkins A, Pantouris G Int J Mol Sci. 2024; 25(23).

PMID: 39684328 PMC: 11641302. DOI: 10.3390/ijms252312617.

The Role of Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (D-DT/MIF-2) in Infections: A Clinical Perspective.

Breidung D, Megas I, Freytag D, Bernhagen J, Grieb G Biomedicines. 2024; 12(1).

PMID: 38275363 PMC: 10813530. DOI: 10.3390/biomedicines12010002.

Allosteric Inhibitors of Macrophage Migration Inhibitory Factor (MIF) Interfere with Apoptosis-Inducing Factor (AIF) Co-Localization to Prevent Parthanatos.

Chen D, Osipyan A, Adriana J, Kader M, Gureev M, Knol C J Med Chem. 2023; 66(13):8767-8781.

PMID: 37352470 PMC: 10350922. DOI: 10.1021/acs.jmedchem.3c00397.

Ligand-induced conformational changes enable intersubunit communications in D-dopachrome tautomerase.

Parkins A, Chen E, Rangel V, Singh M, Xue L, Lisi G Biophys J. 2023; 122(7):1268-1276.

PMID: 36804669 PMC: 10111345. DOI: 10.1016/j.bpj.2023.02.019.

A Cysteine Variant at an Allosteric Site Alters MIF Dynamics and Biological Function in Homo- and Heterotrimeric Assemblies.

Skeens E, Pantouris G, Shah D, Manjula R, Ombrello M, Maluf N Front Mol Biosci. 2022; 9:783669.

PMID: 35252348 PMC: 8893199. DOI: 10.3389/fmolb.2022.783669.

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