Structural insights into the catalytic mechanism of a sacrificial sulfur insertase of the N-type ATP pyrophosphatase family, LarE

Fellner, Matthias; Desguin, Benoît; Hausinger, Robert P.; Hu, Jian

doi:10.1073/pnas.1704967114

Title: Structural insights into the catalytic mechanism of a sacrificial sulfur insertase of the N-type ATP pyrophosphatase family, LarE

Journal Article · Mon Aug 07 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1704967114· OSTI ID:1419864

Fellner, Matthias ^[1]; Desguin, Benoît ^[2];

^[1]; Hu, Jian ^[1]

Michigan State Univ., East Lansing, MI (United States)
Michigan State Univ., East Lansing, MI (United States); Univ. catholique de Louvain, Louvain-La-Neuve (Belgium)

The lar operon in Lactobacillus plantarum encodes five Lar proteins (LarA/B/C/D/E) that collaboratively synthesize and incorporate a niacin-derived Ni-containing cofactor into LarA, an Ni-dependent lactate racemase. Previous studies have established that two molecules of LarE catalyze successive thiolation reactions by donating the sulfur atom of their exclusive cysteine residues to the substrate. Here, the catalytic mechanism of this very unusual sulfur-sacrificing reaction remains elusive. In this work, we present the crystal structures of LarE in ligand-free and several ligand-bound forms, demonstrating that LarE is a member of the N-type ATP pyrophosphatase (PPase) family with a conserved N-terminal ATP PPase domain and a unique C-terminal domain harboring the putative catalytic site. Structural analysis, combined with structure-guided mutagenesis, leads us to propose a catalytic mechanism that establishes LarE as a paradigm for sulfur transfer through sacrificing its catalytic cysteine residue.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Science Foundation (NSF)

Grant/Contract Number:: CHE-1516126

OSTI ID:: 1419864

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 34; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 22 works

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Functional Models of the Nickel Pincer Nucleotide Cofactor of Lactate Racemase Shi, Renyi; Wodrich, Matthew D.; Pan, Hui‐Jie Angewandte Chemie International Edition, Vol. 58, Issue 47 https://doi.org/10.1002/anie.201910490	journal	November 2019
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Biosynthesis of the nickel-pincer nucleotide cofactor of lactate racemase requires a CTP-dependent cyclometallase Desguin, Benoît; Fellner, Matthias; Riant, Olivier Journal of Biological Chemistry, Vol. 293, Issue 32 https://doi.org/10.1074/jbc.ra118.003741	journal	June 2018
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59 BASIC BIOLOGICAL SCIENCES
thiolation
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crystal structure
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catalysis

Title: Structural insights into the catalytic mechanism of a sacrificial sulfur insertase of the N-type ATP pyrophosphatase family, LarE

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