Insights into the smooth-to-rough transitioning in Mycobacterium bolletii unravels a functional Tyr residue conserved in all mycobacterial MmpL family members

被引:96
作者
Bernut, Audrey [1 ]
Viljoen, Albertus [1 ,2 ]
Dupont, Christian [1 ]
Sapriel, Guillaume [3 ]
Blaise, Mickael [1 ]
Bouchier, Christiane [4 ]
Brosch, Roland [5 ]
de Chastellier, Chantal [2 ]
Herrmann, Jean-Louis [3 ]
Kremer, Laurent [1 ,6 ]
机构
[1] Univ Montpellier, CNRS, Ctr Etud Agents Pathogenes & Biotechnol Sante, FRE3689, 1919 Route Mende, F-34293 Montpellier, France
[2] Aix Marseille Univ, Ctr Immunol Marseille Luminy, INSERM, UM2,U1104,CNRS UMR7280, F-13288 Marseille, France
[3] Univ Versailles St Quentin, INSERM, UMR1173, 2 Ave Source Bievre, F-78180 Montigny Le Bretonneux, France
[4] Inst Pasteur, Genopole PF1, 28 Rue Dr Roux, F-75724 Paris, France
[5] Inst Pasteur, Unite Pathogen Mycobacterienne Integree, 25 Rue Dr Roux, F-75724 Paris, France
[6] CPBS, INSERM, F-34293 Montpellier, France
关键词
MULTIDRUG EFFLUX PUMP; NONTUBERCULOUS MYCOBACTERIA; BIOFILM FORMATION; TAXONOMIC STATUS; CYSTIC-FIBROSIS; OUTER-MEMBRANE; CELL-WALL; SP-NOV; ABSCESSUS; TUBERCULOSIS;
D O I
10.1111/mmi.13283
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In mycobacteria, MmpL proteins represent key components that participate in the biosynthesis of the complex cell envelope. Whole genome analysis of a spontaneous rough morphotype variant of Mycobacterium abscessus subsp. bolletii identified a conserved tyrosine that is crucial for the function of MmpL family proteins. Isogenic smooth (S) and rough (R) variants differed by a single mutation linked to a Y842H substitution in MmpL4a. This mutation caused a deficiency in glycopeptidolipid production/transport in the R variant and a gain in the capacity to produce cords in vitro. In zebrafish, increased virulence of the M.bolletiiR variant over the parental S strain was found, involving massive production of serpentine cords, abscess formation and rapid larval death. Importantly, this finding allowed us to demonstrate an essential role of Tyr842 in several different MmpL proteins, including Mycobacterium tuberculosisMmpL3. Structural homology models of MmpL4a and MmpL3 identified two additional critical residues located in the transmembrane regions TM10 and TM4 that are facing each other. We propose that these central residues are part of the proton-motive force that supplies the energy for substrate transport. Hence, we provide important insights into mechanistic/structural aspects of MmpL proteins as lipid transporters and virulence determinants in mycobacteria.
引用
收藏
页码:866 / 883
页数:18
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