The Crystal Structure of Human α₂‐Macroglobulin Reveals a Unique Molecular Cage

Abstract

I'm your Venus: The crystal structure of the human methylamine‐induced form of α2‐macroglobulin (α2M) shows its large central cavity can accommodate two medium‐sized proteinases (see structure, front part clipped off to better show central cavity). Twelve major entrances provide access for small substrates to the cavity and the still‐active trapped “prey”. The structure unveils the molecular basis of the unique “venus flytrap” mechanism of α2M.

Structure of a bacterial α2-macroglobulin reveals mimicry of eukaryotic innate immunity

“…1b). Previous studies with human and E. coli A2M have shown that reaction with methylamine inactivates the thioester and causes a major conformational change in the eukaryotic variant 5,19,32,33,[37][38][39] . To address the issue of a potential conformational change in a bacterial A2M on activation, we solved the crystal structure of methylamine-treated Sa-A2M.…”

“…Protease entrapment occurs through a 'Venus flytrap mechanism' 4,5 involving proteolytic cleavage of the recognized bait region, followed by a large conformational change that blocks the target protease within a cage-like complex. Exposure of the highly reactive thioester site (CXEQ), which associates covalently to the protease, prevents its escape.…”

The structure and function of thioester-containing proteins in arthropods

“…2b) of the three vertebrate complement factors C3–C5 and Ag TEP1 (Janssen et al 2005; Fredslund et al 2006, 2008; Baxter et al 2007; Laursen et al 2010), and the post-activation state (Fig. 2c) of C3 and C5 (C3b, C5b), and MeNH 2 -treated A 2 M (A 2 M-MeNH 2 ) (Janssen et al 2006; Wiesmann et al 2006; Hadders et al 2012; Marrero et al 2012). Distortion of the quaternary structure, such as the pre-activation state of Ag TEP1 and disorder of RBD in the post-activation state of A 2 M, is discussed below.…”

“…MG7 contacts both CUB and MG8 and the whole α chain sits on top of the β-ring, the MG2–MG6 dimer contacting the TED-CUB-MG8 superdomain while MG3 contacts MG7. There is currently no A 2 M crystal structure with an intact thioester bond, but flexible modeling of SAXS and EM data for tetrameric human A 2 M and monomeric E. coli A 2 M (ECAM) support a similar domain arrangement to that of complement and Ag TEP1 (Marrero et al 2012; Neves et al 2012). …”

“…Disruption of the TED–MG8 interface is a key feature in activation, as hydrolysis and aminolysis of the thioester have similar structural and functional consequences as proteolysis (basal complement activity due to hydrolysis is known as ‘tick-over’) (Pangburn and Müller-Eberhard 1980; Isenman et al 1981). During activation, MG7 and MG8 rotate around the central axis of the β-ring; in A 2 M-MeNH 2 , the RBD separates from MG7, becoming flexible relative to the remaining structure (Marrero et al 2012). The β-ring adopts a similar prolate conformation in all post-activation TEP structures, suggesting that it represents a stable conformation for these domains.…”