TY  - JOUR
ID  - open3321
UR  - http://crdd.osdd.net/open/3321/
IS  - 23
A1  - Kumar, Ajay
A1  - Kumar, Rajender
A1  - Boradia, Vishant Mahendra
A1  - Malhotra, Himanshu
A1  - Kumar, Adarsh
A1  - Seth, Sriraj
A1  - Garg, Prabha
A1  - Karthikeyan, Subramanian
A1  - Raje, Manoj
A1  - Iyengar Raje, Chaaya
Y1  - 2024/12//
N2  - 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.
JF  - FEBS J.
VL  - 291
KW  - glyceraldehyde-3-phosphate-dehydrogenase (GAPDH); lactoferrin; plasmin(ogen); protein multifunctionality; transferrin
TI  - Stoichiometry of ligand binding and role of C-terminal lysines in Mycobacterium tuberculosis and human GAPDH multifunctionality
SP  - 5236
EP  - 5255
ER  -