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Energetics of zinc-mediated interactions in the allosteric pathways of metal sensor proteins.

ABSTRACT: A metal-mediated interprotomer hydrogen bond has been implicated in the allosteric mechanism of DNA operator binding in several metal-sensing proteins. Using computational methods, we investigate the energetics of such zinc-mediated interactions in members of the ArsR/SmtB family of proteins (CzrA, SmtB, CadC, and NmtR) and the MarR family zinc-uptake repressor AdcR, which feature similar interactions, but in sites that differ widely in their allosteric responsiveness. We provide novel structural insight into previously uncharacterized allosteric forms of these proteins using computational methodologies. We find this metal-mediated interaction to be significantly stronger (?8 kcal/mol) at functional allosteric metal binding sites compared to a nonresponsive site (CadC) and the apo-proteins. Simulations of the apo-proteins further reveal that the high interaction energy works to overcome the considerable disorder at these hydrogen-bonding sites and functions as a "switch" to lock in a weak DNA-binding conformation once metal is bound. These findings suggest a conserved functional role of metal-mediated second coordination shell hydrogen bonds at allosterically responsive sites in zinc-sensing transcription regulators.

SUBMITTER: Chakravorty DK

PROVIDER: S-EPMC3544337 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Energetics of zinc-mediated interactions in the allosteric pathways of metal sensor proteins.

Chakravorty Dhruva K DK Parker Trent M TM Guerra Alfredo J AJ Sherrill C David CD Giedroc David P DP Merz Kenneth M KM

Journal of the American Chemical Society 20121226 1

A metal-mediated interprotomer hydrogen bond has been implicated in the allosteric mechanism of DNA operator binding in several metal-sensing proteins. Using computational methods, we investigate the energetics of such zinc-mediated interactions in members of the ArsR/SmtB family of proteins (CzrA, SmtB, CadC, and NmtR) and the MarR family zinc-uptake repressor AdcR, which feature similar interactions, but in sites that differ widely in their allosteric responsiveness. We provide novel structura ...[more]

PMID: 23214972

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Project description:Neuronal Calcium Sensors (NCS) are highly conserved proteins specifically expressed in neurons. Calcium (Ca2+)-binding to their EF-hand motifs results in a conformational change, which is crucial for the recognition of a specific target and the downstream biological process. Here we present a comprehensive analysis of the allosteric communication between Ca2+-binding sites and the target interfaces of three NCS, namely NCS1, recoverin (Rec), and GCAP1. In particular, Rec was investigated in different Ca2+-loading states and in complex with a peptide from the Rhodopsin Kinase (GRK1) while NCS1 was studied in a Ca2+-loaded state in complex with either the same GRK1 target or a peptide from the D2 Dopamine receptor. A Protein Structure Network (PSN) accounting for persistent non-covalent interactions between amino acids was built for each protein state based on exhaustive Molecular Dynamics simulations. Structural network analysis helped unveiling the role of key amino acids in allosteric mechanisms and their evolutionary conservation among homologous proteins. Results for NCS1 highlighted allosteric inter-domain interactions between Ca2+-binding motifs and residues involved in target recognition. Robust long range, allosteric protein-target interactions were found also in Rec, in particular originating from the EF3 motif. Interestingly, Tyr 86, involved the hydrophobic packing of the N-terminal domain, was found to be a key residue for both intra- and inter-molecular communication with EF3, regardless of the presence of target or Ca2+ ions. Finally, based on a comprehensive topological PSN analysis for Rec, NCS1, and GCAP1 and multiple sequence alignments with homolog proteins, we propose that an evolution-driven correlation may exist between the amino acids mediating the highest number of persistent interactions (high-degree hubs) and their conservation. Such conservation is apparently fundamental for the specific structural dynamics required in signaling events.

Dataset Information

Energetics of zinc-mediated interactions in the allosteric pathways of metal sensor proteins.

Publications

Energetics of zinc-mediated interactions in the allosteric pathways of metal sensor proteins.

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