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Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior.

ABSTRACT: Allosteric behavior is central to the function of many proteins, enabling molecular machinery, metabolism, signaling and regulation. Recent years have shown that the intrinsic dynamics of allosteric proteins defined by their 3-dimensional architecture or by the topology of inter-residue contacts favors cooperative motions that bear close similarity to structural changes they undergo during their allosteric actions. These conformational motions are usually driven by energetically favorable or soft modes at the low frequency end of the mode spectrum, and they are evolutionarily conserved among orthologs. These observations brought into light evolutionary adaptation mechanisms that help maintain, optimize or regulate allosteric behavior as the evolution from bacterial to higher organisms introduces sequential heterogeneities and structural complexities.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7250723 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior.

Zhang Yan Y Doruker Pemra P Kaynak Burak B Zhang She S Krieger James J Li Hongchun H Bahar Ivet I

Current opinion in structural biology 20191127

Allosteric behavior is central to the function of many proteins, enabling molecular machinery, metabolism, signaling and regulation. Recent years have shown that the intrinsic dynamics of allosteric proteins defined by their 3-dimensional architecture or by the topology of inter-residue contacts favors cooperative motions that bear close similarity to structural changes they undergo during their allosteric actions. These conformational motions are usually driven by energetically favorable or sof ...[more]

PMID: 31785465

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Project description:Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens.IMPORTANCE EptA and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to colistin, a final resort against carbapenem-resistant pathogens. Structural and functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid substrate-recognizing cavities, which explains intrinsic and transferable colistin resistance in gut bacteria. A similar mechanism is proposed for the catalytic activities of EptA and MCR-1 and -2. Together, they constitute a common mechanism for intrinsic and transferable polymyxin resistance.

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Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior.

Publications

Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior.

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