Inhibition of Yeast Ribonucleotide Reductase by Sml1 Depends on the Allosteric State of the Enzyme

Authors

Tessianna A. Misko, Case Western Reserve University
Sanath R. Wijerathna, Case Western Reserve University
Tomas Radivoyevitch, Cleveland Clinic Foundation
Anthony J. Berdis, Cleveland State UniversityFollow
Md. Faiz Ahmad, Case Western Reserve University
Michael E. Harris, Case Western Reserve University
Chris G. Dealwis, Case Western Reserve UniversityFollow

Document Type

Article

Publication Date

6-2016

Publication Title

FEBS Letters

Abstract

Sml1 is an intrinsically disordered protein inhibitor of Saccharomyces cerevisiae ribonucleotide reductase (ScRR1), but its inhibition mechanism is poorly understood. RR reduces ribonucleoside diphosphates to their deoxy forms, and balances the nucleotide pool. Multiple turnover kinetics show that Sml1 inhibition of dGTP/ADP- and ATP/CDP-bound ScRR follows a mixed inhibition mechanism. However, Sml1 cooperatively binds to the ES complex in the dGTP/ADP form, whereas with ATP/CDP, Sml1 binds weakly and noncooperatively. Gel filtration and mutagenesis studies indicate that Sml1 does not alter the oligomerization equilibrium and the CXXC motif is not involved in the inhibition. The data suggest that Sml1 is an allosteric inhibitor.

Comments

Funding was provided by the NIH [grant numbers R01GM100887, R01CA100827 and 5R25CA148052-05.]

Recommended Citation

Misko, T. A.; Wijerathna, S. R.; Radivoyevitch, T.; Berdis, A. J.; Ahmad, M. F.; Harris, M. E.; Dealwis, C. G. Inhibition of yeast ribonucleotide reductase by Sml1 depends on the allosteric state of the enzyme. FEBS Lett. 2016, 590, 1704-1712.

DOI

10.1002/1873-3468.12207

Volume

590

Issue

12