Allosteric regulation and substrate activation in cytosolic nucleotidaseIIfromLegionella pneumophila

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Abstract

Cytosolic nucleotidase II ( cN ‐ II ) from L egionella pneumophila ( L p) catalyzes the hydrolysis of GMP and d GMP displaying sigmoidal curves, whereas catalysis of IMP hydrolysis displayed a biphasic curve in the initial rate versus substrate concentration plots. Allosteric modulators of mammalian c N ‐ II did not activate L pc N ‐ II although GTP , GDP and the substrate GMP were specific activators. Crystal structures of the tetrameric L pc N ‐ II revealed an activator‐binding site at the dimer interface. A double mutation in this allosteric‐binding site abolished activation, confirming the structural observations. The substrate GMP acting as an activator, partitioning between the allosteric and active site, is the basis for the sigmoidicity of the initial velocity versus GMP concentration plot. The L pc N ‐ II tetramer showed differences in subunit organization upon activator binding that are absent in the activator‐bound human c N ‐ II structure. This is the first observation of a structural change induced by activator binding in c N ‐ II that may be the molecular mechanism for enzyme activation. Database The coordinates and structure factors reported in this paper have been submitted to the Protein Data Bank under the accession numbers 2BDE and 4G63 . The accession number of GMP complexed L pc N ‐ II is 4OHF . Structured digital abstract LpcN-II and LpcN-II bind by molecular sieving ( View interaction ) LpcN-II and LpcN-II bind by x-ray crystallography ( View interaction ) [Structured digital abstract was added on 5 March 2014 after original online publication]

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