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A nucleotide-dependent conformational switch controls the polymerization of human IMP dehydrogenases to modulate their catalytic activity

DOI: 10.1016/j.jmb.2019.01.020 DOI Help

Authors: David Fernandez-justel (Universidad de Salamanca) , Rafael Nunez (Centro de Investigaciones Biológicas (CIB), Spanish National Research Council (CSIC)) , Jaime Martin-benito (Centro de Investigaciones Biológicas (CIB), Spanish National Research Council (CSIC)) , David Jimeno (Instituto de Biología Molecular y Celular del Cáncer (CSIC-Universidad de Salamanca)) , Adrián González-lópez (Universidad de Salamanca) , Eva María Soriano (Universidad de Salamanca) , José Luis Revuelta (Universidad de Salamanca) , Ruben M. Buey (Universidad de Salamanca)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 10121

Abstract: IMP dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH has been studied for decades but it has only been within the last years that we are starting to understand the complexity of the mechanisms of its physiological regulation. Here, we report structural and functional insights into how adenine and guanine nucleotides control a conformational switch that modulates the assembly of the two human IMPDH enzymes into cytoophidia and allosterically regulates their catalytic activity. In vitro reconstituted micron-length cytoophidia-like structures show catalytic activity comparable to unassembled IMPDH but, in turn, are more resistant to GTP/GDP allosteric inhibition. Therefore, IMPDH cytoophidia formation facilitates the accumulation of high levels of guanine nucleotides when the cell requires it. Finally, we demonstrate that most of the IMPDH retinopathy-associated mutations abrogate GTP/GDP-induced allosteric inhibition and alter cytoophidia dynamics.

Journal Keywords: IMP dehydrogenase; Cytoophidia; Conformational switch; Allosteric regulation; X-ray crystallography and scattering

Subject Areas: Biology and Bio-materials

Instruments: B21-High Throughput SAXS , I03-Macromolecular Crystallography