Abstract
Iron is crucial for the survival of living cells, particularly the human pathogen Mycobacterium tuberculosis (M.tb) which uses multiple strategies to acquire and store iron. M.tb synthesizes high affinity iron chelators (siderophores), these extract iron from host iron carrier proteins such as transferrin (Tf) and lactoferrin (Lf). Recent studies have revealed that M.tb may also relocate several housekeeping proteins to the cell surface for capture and internalization of host iron carrier protein transferrin. One of the identified receptors is the glycolytic enzyme Glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This conserved multifunctional protein has been identified as a virulence factor in several other bacterial species. Considering the close structural and functional homology between the two major human iron carrier proteins (Tf and Lf) and the fact that Lf is abundantly present in lung fluid (unlike Tf which is present in plasma), we evaluated whether GAPDH also functions as a dual receptor for Lf. The current study demonstrates that human Lf is sequestered at the bacterial surface by GAPDH. The affinity of Lf-GAPDH (31.7 ± 1.68 nM) is higher as compared to Tf-GAPDH (160 ± 24 nM). Two GAPDH mutants were analyzed for their enzymatic activity and interaction with Lf. Lastly, the present computational studies offer the first significant insights for the 3D structure of monomers and assembled tetramer with the associated co-factor NAD+. Sequence analysis and structural modeling identified the surface exposed, evolutionarily conserved and functional residues and predicted the effect of mutagenesis on GAPDH.
Highlights
Iron acquisition is vital for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis
Due to its intracellular location, M. tuberculosis faces a unique challenge in acquiring iron from within the host cell
It adopts multiple strategies to acquire this essential micronutrient from host iron carrier/storage proteins such as Tf, Lf, ferritin, and hemoglobin
Summary
Iron acquisition is vital for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis. In order to survive and replicate within the iron restricted intracellular environment of the host cell, these pathogens utilize multiple strategies to pilfer iron from host resources. The M.tb Tf receptors identified included several conserved proteins namely Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Rv1436); Lactate dehydrogenase (Rv1872c); Iron regulated Elongation factor tu (Rv0685); Acyl desaturase (Rv0824c); 50S ribosomal protein L2rplB (Rv0704); 50S ribosomal protein L1rplA (Rv0641) (Boradia et al, 2014). Earlier GAPDH has been identified as a dual receptor for both Tf and Lf in mammalian cells (Raje et al, 2007; Rawat et al, 2012). GAPDH plays analogous roles in Tf acquisition of iron by M.tb as well as its human host (Boradia et al, 2014)
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