Alpha-2-macroglobulins (A2Ms) are plasma proteins that trap and inhibit a broad range of proteases and are major components of the eukaryotic innate immune system. Surprisingly, A2M-like proteins were identified in pathogenically invasive bacteria and species that colonize higher eukaryotes. Bacterial A2Ms are located in the periplasm where they are believed to provide protection to the cell by trapping external proteases through a covalent interaction with an activated thioester. Two types of bacterial A2Ms have been identified : Type I, much like the eukaryotic form, displays a conserved thioester that is essential for protease targeting, and Type II, which lacks the thioester and is ubiquitous in Gram-negatives.
Our group solved the first structure of a bacterial macroglobulin (Wong & Dessen 2014). The structure revealed thirteen domains whose arrangement displays high similarity to proteins involved in eukaryotic immune defense.
Bacterial macroglobulins display 13 domains. (Top) Schematic arrangement of the S. typhimurium A2M, which harbors over 1600 residues that fold mostly into beta-sheet-carrying domains (bottom). The only exception is the thioester domain (TED), which is mostly helical (purple), and harbors the thioester bond that attacks target proteases.
We subsequently characterized the Type II A2M MagD and a complex it generates with 4 other Mag proteins in P. aeruginosa. We recently showed that MagC has a NlpC-like fold, binds peptidoglycan (PG), and could serve as an anchor between the macroglobulin and the PG.
P. aeruginosa MagC is structurally similar to other PG binding NlpC/P60-like proteins (Zouhir et al., 2021).
Zouhir S, Contreras-Martel C, Trindade DM, Attrée I, Dessen A, Macheboeuf P (2021). MagC is a NlpC/P60-like member of the $\alpha$-2-macroglobulin Mag complex of Pseudomonas aeruginosa that interacts with peptidoglycan. FEBS Lett. 5959, 2034-2046.
Zouhir S, Robert-Genthon M, Trindade DM, Job V, Nedeljković M, Breyton C, Ebel C, Attrée I, Dessen A (2018). Assembly of an atypical $\alpha$-macroglobulin from Pseudomonas aeruginosa. Sci. Rep. 8, 527.
Wong, SG and Dessen A (2014). Structure of a bacterial $\alpha$-2-macroglobulin reveals mimicry of eukaryotic innate immunity. Nature Comm. 5, 4917.