The MmpL Protein Family

Jain, Madhulika; Chow, Eric D.; Cox, Jeffery S.

doi:10.1128/9781555815783.ch12

Cited by 12 publications

(19 citation statements)

References 53 publications

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“…; Jain et al. ), MmpL11tb appears to transport monomeromycoloyl diacylglycerol (MMDAG) and mycolate ester wax to the bacterial surface, whereas MmpL4 and MmpL5 are required for the export of mycobactins (Wells et al. ).…”

Section: Discussionmentioning

confidence: 99%

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RND transporters protect Corynebacterium glutamicum from antibiotics by assembling the outer membrane

Yang

Belardinelli

et al. 2014

MicrobiologyOpen

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Corynebacterium–Mycobacterium–Nocardia (CMN) group are the causative agents of a broad spectrum of diseases in humans. A distinctive feature of these Gram-positive bacteria is the presence of an outer membrane of unique structure and composition. Recently, resistance–nodulation–division (RND) transporters (nicknamed MmpLs, Mycobacterial membrane protein Large) have emerged as major contributors to the biogenesis of the outer membranes in mycobacteria and as promising drug targets. In this study, we investigated the role of RND transporters in the physiology of Corynebacterium glutamicum and analyzed properties of these proteins. Our results show that in contrast to Gram-negative species, in which RND transporters actively extrude antibiotics from cells, in C. glutamicum and relatives these transporters protect cells from antibiotics by playing essential roles in the biogenesis of the low-permeability barrier of the outer membrane. Conditional C. glutamicum mutants lacking RND proteins and with the controlled expression of either NCgl2769 (CmpL1) or NCgl0228 (CmpL4) are hypersusceptible to multiple antibiotics, have growth deficiencies in minimal medium and accumulate intracellularly trehalose monocorynomycolates, free corynomycolates, and the previously uncharacterized corynomycolate-containing lipid. Our results also suggest that similar to other RND transporters, Corynebacterial membrane proteins Large (CmpLs) functions are dependent on a proton-motive force.

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Section: Discussionmentioning

confidence: 99%

“…The synthesis and transport of CMN surface lipids requires transporters belonging to the resistance–nodulation–cell division (RND) superfamily, nicknamed MmpLs (Mycobacterial membrane protein Large) in mycobacteria (Jain et al. ; Grzegorzewicz et al. ; Varela et al.…”

Section: Introductionmentioning

confidence: 99%

RND transporters protect Corynebacterium glutamicum from antibiotics by assembling the outer membrane

Yang

Belardinelli

et al. 2014

MicrobiologyOpen

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“…Unlike AcrB-type multidrug efflux pumps, the MmpL/CmpL proteins of Corynebacteriaceae appear to export endogenous lipophilic molecules rather than exogenous ones, and to display a relatively narrow substrate specificity. 3-4,11-15 Other than impacting the composition of the mycobacterial cell envelope and thus, indirectly, its permeability to biocides, the MmpL proteins of Mtb do not seem to play an active role in drug resistance, exception made of MmpL5 that participates in the active efflux of clofazimine, bedaquiline and azole drugs. 4,16-21 A decade of functional studies indicate that MmpL proteins have specialized in the translocation of physiologically essential and/or biologically active secreted and outer membrane (OM) constituents, including (glyco)lipids and siderophores.…”

mentioning

confidence: 99%

“…4,16-21 A decade of functional studies indicate that MmpL proteins have specialized in the translocation of physiologically essential and/or biologically active secreted and outer membrane (OM) constituents, including (glyco)lipids and siderophores. 3-4,11-15,22 On the basis of their heme-binding properties in vitro , two MmpL proteins, MmpL3 and MmpL11, were further proposed to be involved in a heme-iron acquisition system. 23-24 The structure of one of the two soluble periplasmic domains of MmpL11 was solved 6 , a transport mechanism based on dynamics simulation was proposed for MmpL5 25 and the use of prediction algorithms yielded different topological models for MmpL3 and other MmpL proteins.…”

mentioning

confidence: 99%

Structure–Function Profile of MmpL3, the Essential Mycolic Acid Transporter from Mycobacterium tuberculosis

et al. 2016

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The MmpL family of proteins translocates complex (glyco)lipids and siderophores across the cell envelope of mycobacteria and closely related Corynebacteriaceae, and plays important roles in the biogenesis of the outer membrane of these organisms. Despite their significance in the physiology and virulence of Mycobacterium tuberculosis, and from the perspective of developing novel antituberculosis agents, little is known about their structure and mechanism of translocation. In this study, the essential mycobacterial mycolic acid transporter, MmpL3, and its ortholog in Corynebacterium glutamicum, CmpL1, were investigated as prototypical MmpL proteins to gain insight into the transmembrane topology, tertiary and quaternary structures, and functional regions of this transporter family. Our combined genetic, biochemical and biophysical studies indicate that MmpL3 and CmpL1 are structurally similar to Gram-negative Resistance-Nodulation and Division efflux pumps. They harbor twelve transmembrane segments interrupted by two large soluble periplasmic domains, and function as homotrimers to export long-chain (C22-C90) mycolic acids, possibly in their acetylated form, esterified to trehalose. The mapping of a number of functional residues within the middle region of the transmembrane domain of MmpL3 shows a striking overlap with mutations associated with resistance to MmpL3 inhibitors. Our results suggest that structurally diverse inhibitors of MmpL3 all target the proton translocation path of the transporter and that multi-resistance to these inhibitors is enabled by conformational changes in MmpL3.

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“…14; Table 3). The MmpL7 protein belongs to the RND (Resistance, Nodulation and cell Division) superfamily of transporters [251]. Like other members of this family, MmpL7 is predicted to consist of twelve transmembrane domains and two large soluble periplasmic loops.…”

Section: Phthiocerol Dimycocerosates Phenolic Glycolipids and Rementioning

confidence: 99%

Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids

2014

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This chapter summarizes what is currently known of the structures, physiological roles, involvement in pathogenicity and biogenesis of a variety of non-covalently bound cell envelope lipids and glycoconjugates of Mycobacterium tuberculosis and other Mycobacterium species. Topics addressed in this chapter include phospholipids; phosphatidylinositol mannosides; triglycerides; isoprenoids and related compounds (polyprenyl phosphate, menaquinones, carotenoids, non-carotenoid cyclic isoprenoids); acyltrehaloses (lipooligosaccharides, trehalose mono- and di-mycolates, sulfolipids, di- and poly-acyltrehaloses); mannosyl-beta-1-phosphomycoketides; glycopeptidolipids; phthiocerol dimycocerosates, para-hydroxybenzoic acids and phenolic glycolipids; mycobactins; mycolactones; and capsular polysaccharides.

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The MmpL Protein Family

Cited by 12 publications

References 53 publications

RND transporters protect Corynebacterium glutamicum from antibiotics by assembling the outer membrane

RND transporters protect Corynebacterium glutamicum from antibiotics by assembling the outer membrane

Structure–Function Profile of MmpL3, the Essential Mycolic Acid Transporter from Mycobacterium tuberculosis

Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids

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