A Trap-Door Mechanism for Zinc Acquisition by Streptococcus pneumoniae AdcA.

Luo, Z; Morey, JR; Deplazes, E; Motygullina, A; Tan, A; Ganio, K; Neville, SL; Eleftheriadis, N; Isselstein, M; Pederick, VG; Paton, JC; Cordes, T; Harmer, JR; Kobe, B; McDevitt, CA

A Trap-Door Mechanism for Zinc Acquisition by Streptococcus pneumoniae AdcA.

Luo, Z Morey, JR Deplazes, E

Motygullina, A Tan, A Ganio, K Neville, SL Eleftheriadis, N Isselstein, M Pederick, VG Paton, JC Cordes, T Harmer, JR Kobe, B McDevitt, CA

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Publisher:: American Society for Microbiology
Publication Type:: Journal Article
Citation:: mBio, 2021, 12, (1), pp. 1-14
Issue Date:: 2021-02-02

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Field	Value	Language
dc.contributor.author	Luo, Z
dc.contributor.author	Morey, JR
dc.contributor.author	Deplazes, E https://orcid.org/0000-0003-2052-5536
dc.contributor.author	Motygullina, A
dc.contributor.author	Tan, A
dc.contributor.author	Ganio, K
dc.contributor.author	Neville, SL
dc.contributor.author	Eleftheriadis, N
dc.contributor.author	Isselstein, M
dc.contributor.author	Pederick, VG
dc.contributor.author	Paton, JC
dc.contributor.author	Cordes, T
dc.contributor.author	Harmer, JR
dc.contributor.author	Kobe, B
dc.contributor.author	McDevitt, CA
dc.date.accessioned	2022-01-07T02:49:42Z
dc.date.available	2022-01-07T02:49:42Z
dc.date.issued	2021-02-02
dc.identifier.citation	mBio, 2021, 12, (1), pp. 1-14
dc.identifier.issn	2150-7511
dc.identifier.issn	2150-7511
dc.identifier.uri	http://hdl.handle.net/10453/152809
dc.description.abstract	Zinc is an essential element in all domains of life. Nonetheless, how prokaryotes achieve selective acquisition of zinc from the extracellular environment remains poorly understood. Here, we elucidate a novel mechanism for zinc-binding in AdcA, a solute-binding protein of Streptococcus pneumoniae. Crystal structure analyses reveal the two-domain organization of the protein and show that only the N-terminal domain (AdcAN) is necessary for zinc import. Zinc binding induces only minor changes in the global protein conformation of AdcA and stabilizes a highly mobile loop within the AdcAN domain. This loop region, which is conserved in zinc-specific solute-binding proteins, facilitates closure of the AdcAN binding site and is crucial for zinc acquisition. Collectively, these findings elucidate the structural and functional basis of selective zinc uptake in prokaryotes. IMPORTANCE Zinc is an essential nutrient for the virulence of bacterial pathogens such as Streptococcus pneumoniae. Many Gram-positive bacteria use a two-domain lipoprotein for zinc acquisition, but how this class of metal-recruiting proteins acquire zinc and interact with the uptake machinery has remained poorly defined. We report the first structure of a two-domain lipoprotein, AdcA from S. pneumoniae, and use computational, spectroscopic, and microbiological approaches to provide new insights into the functional basis of zinc recruitment. Our findings reveal that AdcA employs a novel mechanism for zinc binding that we have termed the “trap-door” mechanism, and we show how the static metal-binding site of the protein, which confers its selectivity for zinc ions, is combined with a dynamic surface element to facilitate zinc recruitment and import into the bacterium. Together, these findings expand our understanding of how bacteria acquire zinc from the environment and provide a foundation for inhibiting this process, through antimicrobial targeting of the dynamic structural elements to block bacterial zinc scavenging.
dc.format	Electronic
dc.language	eng
dc.publisher	American Society for Microbiology
dc.relation	http://purl.org/au-research/grants/nhmrc/1122582
dc.relation.ispartof	mBio
dc.relation.isbasedon	10.1128/mbio.01958-20
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0605 Microbiology
dc.subject.mesh	ATP-Binding Cassette Transporters
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Binding Sites
dc.subject.mesh	Molecular Dynamics Simulation
dc.subject.mesh	Protein Conformation
dc.subject.mesh	Protein Domains
dc.subject.mesh	Streptococcus pneumoniae
dc.subject.mesh	Zinc
dc.subject.mesh	Streptococcus pneumoniae
dc.subject.mesh	Zinc
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	ATP-Binding Cassette Transporters
dc.subject.mesh	Binding Sites
dc.subject.mesh	Protein Conformation
dc.subject.mesh	Molecular Dynamics Simulation
dc.subject.mesh	Protein Domains
dc.title	A Trap-Door Mechanism for Zinc Acquisition by Streptococcus pneumoniae AdcA.
dc.type	Journal Article
utslib.citation.volume	12
utslib.location.activity	United States
utslib.for	0605 Microbiology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2022-01-07T02:49:37Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	12
utslib.citation.issue	1

Abstract:

Zinc is an essential element in all domains of life. Nonetheless, how prokaryotes achieve selective acquisition of zinc from the extracellular environment remains poorly understood. Here, we elucidate a novel mechanism for zinc-binding in AdcA, a solute-binding protein of Streptococcus pneumoniae. Crystal structure analyses reveal the two-domain organization of the protein and show that only the N-terminal domain (AdcAN) is necessary for zinc import. Zinc binding induces only minor changes in the global protein conformation of AdcA and stabilizes a highly mobile loop within the AdcAN domain. This loop region, which is conserved in zinc-specific solute-binding proteins, facilitates closure of the AdcAN binding site and is crucial for zinc acquisition. Collectively, these findings elucidate the structural and functional basis of selective zinc uptake in prokaryotes. IMPORTANCE Zinc is an essential nutrient for the virulence of bacterial pathogens such as Streptococcus pneumoniae. Many Gram-positive bacteria use a two-domain lipoprotein for zinc acquisition, but how this class of metal-recruiting proteins acquire zinc and interact with the uptake machinery has remained poorly defined. We report the first structure of a two-domain lipoprotein, AdcA from S. pneumoniae, and use computational, spectroscopic, and microbiological approaches to provide new insights into the functional basis of zinc recruitment. Our findings reveal that AdcA employs a novel mechanism for zinc binding that we have termed the “trap-door” mechanism, and we show how the static metal-binding site of the protein, which confers its selectivity for zinc ions, is combined with a dynamic surface element to facilitate zinc recruitment and import into the bacterium. Together, these findings expand our understanding of how bacteria acquire zinc from the environment and provide a foundation for inhibiting this process, through antimicrobial targeting of the dynamic structural elements to block bacterial zinc scavenging.

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http://hdl.handle.net/10453/152809