Molecular Dynamics Simulations of Selective Metabolite Transport across the Propanediol Bacterial Microcompartment Shell

Park, Jiyong; Chun, Sunny; Bobik, Thomas A.; Houk, K. N.; Yeates, T.O.

doi:10.1021/acs.jpcb.7b07232

Cited by 36 publications

(31 citation statements)

References 38 publications

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“…3C-3F), indicating the importance of residues Ser39, Lys36 and Arg11 in mediating metabolite flux through the pore. Consistently, recent studies on 1,2-propanediol utilization (1,2-PDU) microcompartments have also verified the role of the equivalent Ser40 of the shell hexamer PduA in channeling metabolite traffic 32,33 . Given that the Ser39, Lys36 and Arg11 residues are conserved among orthologous BMC-H members as demonstrated by protein sequence alignment ( Supplementary Fig.…”

Section: Molecular Transport Of the Pore Is Mediated By Electrostaticsupporting

confidence: 68%

Molecular simulations unravel the molecular principles that mediate selective permeability of carboxysome shell protein

Faulkner

Szabó

Weetman

et al. 2020

Preprint

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Bacterial microcompartments (BMCs) are nanoscale proteinaceous organelles that encapsulate enzymes from the cytoplasm using an icosahedral protein shell that resembles viral capsids. Of particular interest are the carboxysomes (CBs), which sequester the CO 2 -fixing enzymes ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) to enhance carbon assimilation. The carboxysome shell serves as a semi-permeable barrier for passage of metabolites in and out of the carboxysome to enhance CO 2 fixation. How the protein shell directs influx and efflux of molecules in an effective manner has remained elusive. Here we use molecular dynamics and umbrella sampling calculations to determine the free-energy profiles of the metabolic substrates, bicarbonate, CO 2 and ribulose bisphosphate and the product 3-phosphoglycerate associated with their transition through the major carboxysome shell protein CcmK2. We elucidate the electrostatic charge-based permeability and key amino acid residues of CcmK2 functioning in mediating molecular transit through the central pore. Conformational changes of the loops forming the central pore may also be required for transit of specific metabolites. The importance of these in-silico findings is validated experimentally by site-directed mutagenesis of the key CcmK2 residue Serine 39. This study provides insight into the mechanism that mediates molecular transport through the shells of carboxysomes, applicable to other BMCs. It also offers a predictive approach to investigate and manipulate the shell permeability, with the intend of engineering BMC-based metabolic modules for new functions in synthetic biology.

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Section: Molecular Transport Of the Pore Is Mediated By Electrostaticsupporting

confidence: 68%

Molecular simulations unravel the molecular principles that mediate selective permeability of carboxysome shell protein

Faulkner

Szabó

Weetman

et al. 2020

Preprint

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“…Hexameric proteins known as microcompartment shell proteins form a tightly packed layer to constitute bacterial microcompartments (BMCs). These proteins tend to assemble into cyclic hexamers and have narrow central pores with diffusive molecular transport taking place via these pores [ 49 ]. Two of the lactobacilli, Lbr and Lre, have homologs of TC subclass 1.S.…”

Section: Resultsmentioning

confidence: 99%

Comparative Genomics of the Transport Proteins of Ten Lactobacillus Strains

Zafar

Saier

2020

Genes

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The genus Lactobacillus includes species that may inhabit different anatomical locations in the human body, but the greatest percentage of its species are inhabitants of the gut. Lactobacilli are well known for their probiotic characteristics, although some species may become pathogenic and exert negative effects on human health. The transportome of an organism consists of the sum of the transport proteins encoded within its genome, and studies on the transportome help in the understanding of the various physiological processes taking place in the cell. In this communication we analyze the transport proteins and predict probable substrate specificities of ten Lactobacillus strains. Six of these strains (L. brevis, L. bulgaricus, L. crispatus, L. gasseri, L. reuteri, and L. ruminis) are currently believed to be only probiotic (OP). The remaining four strains (L. acidophilus, L. paracasei, L. planatarum, and L. rhamnosus) can play dual roles, being both probiotic and pathogenic (PAP). The characteristics of the transport systems found in these bacteria were compared with strains (E. coli, Salmonella, and Bacteroides) from our previous studies. Overall, the ten lactobacilli contain high numbers of amino acid transporters, but the PAP strains contain higher number of sugar, amino acid and peptide transporters as well as drug exporters than their OP counterparts. Moreover, some of the OP strains contain pore-forming toxins and drug exporters similar to those of the PAP strains, thus indicative of yet unrecognized pathogenic potential. The transportomes of the lactobacilli seem to be finely tuned according to the extracellular and probiotic lifestyles of these organisms. Taken together, the results of this study help to reveal the physiological and pathogenic potential of common prokaryotic residents in the human body.

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“…MCP operons typically encode a single BMV protein that is thought to help impart curvature to the shell and multiple BMC domain proteins which fulfill various functional roles (44,47). Hexameric BMC domain proteins have central pores that mediate the selective transport of small molecules across the MCP shell (43,48,49). The trimeric class of BMC domain proteins includes members proposed to have allosterically gated pores for the transport of larger molecules, as well as members with FeS clusters thought to mediate electron transfer across the MCP shell (50)(51)(52)(53)(54)(55)(56)(57).…”

mentioning

confidence: 99%

A Bacterial Microcompartment Is Used for Choline Fermentation by Escherichia coli 536

et al. 2018

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Bacterial choline degradation in the human gut has been associated with cancer and heart disease. In addition, recent studies found that a bacterial microcompartment is involved in choline utilization by and species. However, many aspects of this process have not been fully defined. Here, we investigate choline degradation by the uropathogen 536. Growth studies indicated 536 degrades choline primarily by fermentation. Electron microscopy indicated that a bacterial microcompartment was used for this process. Bioinformatic analyses suggested that the choline utilization () gene cluster of 536 includes two operons, one containing three genes and a main operon of 13 genes. Regulatory studies indicate that the gene encodes a positive transcriptional regulator required for induction of the main operon in response to choline supplementation. Each of the 16 genes in the cluster was individually deleted, and phenotypes were examined. The ,, ,, ,, , and genes were required for choline degradation, but the remaining genes of the cluster were not essential under the conditions used. The reasons for these varied phenotypes are discussed. Here, we investigate choline degradation in 536. These studies provide a basis for understanding a new type of bacterial microcompartment and may provide deeper insight into the link between choline degradation in the human gut and cancer and heart disease. These are also the first studies of choline degradation in 536, an organism for which sophisticated genetic analysis methods are available. In addition, the gene cluster of 536 is located in pathogenicity island II (PAI-II) and hence might contribute to pathogenesis.

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Molecular Dynamics Simulations of Selective Metabolite Transport across the Propanediol Bacterial Microcompartment Shell

Cited by 36 publications

References 38 publications

Molecular simulations unravel the molecular principles that mediate selective permeability of carboxysome shell protein

Molecular simulations unravel the molecular principles that mediate selective permeability of carboxysome shell protein

Comparative Genomics of the Transport Proteins of Ten Lactobacillus Strains

A Bacterial Microcompartment Is Used for Choline Fermentation by Escherichia coli 536

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