creators_name: Kumar, Ajay
creators_name: Kumar, Rajender
creators_name: Boradia, Vishant Mahendra
creators_name: Malhotra, Himanshu
creators_name: Kumar, Adarsh
creators_name: Seth, Sriraj
creators_name: Garg, Prabha
creators_name: Karthikeyan, Subramanian
creators_name: Raje, Manoj
creators_name: Iyengar Raje, Chaaya
type: article
datestamp: 2026-02-07 04:35:19
lastmod: 2026-02-07 04:35:19
metadata_visibility: show
title: Stoichiometry of ligand binding and role of C-terminal lysines in Mycobacterium tuberculosis and human GAPDH multifunctionality
keywords: glyceraldehyde-3-phosphate-dehydrogenase (GAPDH); lactoferrin; plasmin(ogen); protein multifunctionality; transferrin
abstract: Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH; EC1.2.1.12) has several functions in Mycobacterium tuberculosis (Mtb) and the human host. Apart from its role in glycolysis, it serves both as a cell surface and a secreted receptor for plasmin(ogen) (Plg/Plm), transferrin (Tf), and lactoferrin (Lf). Plg sequestration by Mtb GAPDH facilitates bacterial adhesion and tissue invasion, while an equivalent interaction with host GAPDH regulates immune cell migration. In both, host and microbe, internalization of Tf/Lf-GAPDH complexes serves as a route for iron acquisition. To date, the structure of Mtb GAPDH or the residues involved in these moonlighting interactions have not been identified. This study provides the first known X-ray crystal structure of Mtb GAPDH. Through further mutagenesis and functional assays, we found that the C-terminal lysines of Mtb and human GAPDH affect enzyme activity and ligand binding. We also establish the stoichiometry of Plg, Tf and Lf interactions with the GAPDH tetramer. Lastly, molecular simulation studies reveal the interactions of the C-terminal lysine residues.
date: 2024-12
publication: FEBS J.
volume: 291
number: 23
pagerange: 5236-5255
citation:   Kumar, Ajay and Kumar, Rajender and Boradia, Vishant Mahendra and Malhotra, Himanshu and Kumar, Adarsh and Seth, Sriraj and Garg, Prabha and Karthikeyan, Subramanian and Raje, Manoj and Iyengar Raje, Chaaya  (2024) Stoichiometry of ligand binding and role of C-terminal lysines in Mycobacterium tuberculosis and human GAPDH multifunctionality.  FEBS J., 291 (23).  pp. 5236-5255.