Crystal structure of the putative cell-wall lipoglycan biosynthesis protein LmcA from Mycobacterium smegmatis.
Onisha PatelRajini BrammananthWeiwen DaiSantosh PanjikarRoss L CoppelIsabelle S LucetPaul K CrellinPublished in: Acta crystallographica. Section D, Structural biology (2022)
The bacterial genus Mycobacterium includes important pathogens, most notably M. tuberculosis, which infects one-quarter of the entire human population, resulting in around 1.4 million deaths from tuberculosis each year. Mycobacteria, and the closely related corynebacteria, synthesize a class of abundant glycolipids, the phosphatidyl-myo-inositol mannosides (PIMs). PIMs serve as membrane anchors for hyperglycosylated species, lipomannan (LM) and lipoarabinomannan (LAM), which are surface-exposed and modulate the host immune response. Previously, in studies using the model species Corynebacterium glutamicum, NCgl2760 was identified as a novel membrane protein that is required for the synthesis of full-length LM and LAM. Here, the first crystal structure of its ortholog in Mycobacterium smegmatis, MSMEG_0317, is reported at 1.8 Å resolution. The structure revealed an elongated β-barrel fold enclosing two distinct cavities and one α-helix extending away from the β-barrel core, resembling a `cone with a flake' arrangement. Through xenon derivatization and structural comparison with AlphaFold2-derived predictions of the M. tuberculosis homolog Rv0227c, structural elements were identified that may undergo conformational changes to switch from `closed' to `open' conformations, allowing cavity access. An AlphaFold2-derived NCgl2760 model predicted a smaller β-barrel core with an enclosed central cavity, suggesting that all three proteins, which were collectively termed LmcA, may have a common mechanism of ligand binding through these cavities. These findings provide new structural insights into the biosynthetic pathway for a family of surface lipoglycans with important roles in mycobacterial pathogenesis.
Keyphrases
- mycobacterium tuberculosis
- cell wall
- pulmonary tuberculosis
- immune response
- endothelial cells
- single molecule
- minimally invasive
- ms ms
- molecular dynamics simulations
- single cell
- liquid chromatography tandem mass spectrometry
- high performance liquid chromatography
- simultaneous determination
- protein protein
- small molecule
- binding protein
- amino acid
- induced pluripotent stem cells
- pluripotent stem cells
- gas chromatography
- electronic health record
- antiretroviral therapy