Anthrax toxin receptor 2 (ANTXR2) (ANTXR2 or CMG2)

Anthrax toxin receptor 2 (ANTXR2), also called capillary morphogenesis protein 2 (CMG2), is a type I transmembrane receptor protein containing von Willebrand factor A and immunoglobulin-like extracellular domains. ANTXR2 functions as the major cellular receptor for anthrax toxin protective antigen in vivo, facilitating toxin entry into host cells through receptor-mediated endocytosis and acting as a molecular clamp to regulate pH-dependent pore formation within endosomes[1][7]. Beyond its role in anthrax pathogenesis, ANTXR2 serves important physiological functions including interaction with extracellular matrix proteins (collagen IV and laminin), regulation of basement membrane integrity, and involvement in capillary formation[9][13]. The receptor demonstrates extremely high-affinity binding to anthrax toxin (Kd ~200 pM), making it the dominant mediator of anthrax lethality[2][7]. Mutations in ANTXR2 cause genetic disorders characterized by extracellular matrix defects, including juvenile hyaline fibromatosis and infantile systemic hyalinosis, highlighting the protein's essential physiological roles beyond toxin recognition[2][4]. The structural and functional properties of ANTXR2 make it a potential therapeutic target for anthrax infection, though any intervention must account for its critical roles in normal tissue homeostasis and vascular development.

Other names

Capillary morphogenesis protein 2 (CMG2)Anthrax toxin receptor cell adhesion molecule 2ANTXR cell adhesion molecule 2

ANTXR2 functions by binding with extremely high affinity (Kd ~200 pM) to the anthrax toxin protective antigen (PA), significantly higher than ANTXR1. Following PA binding, the toxin-receptor complexes are internalized into cells via receptor-mediated, clathrin-dependent endocytosis. The receptor's cytosolic domain undergoes post-translational modifications (ubiquitination and phosphorylation). Within the endosome, the acidic environment triggers a conformational rearrangement of the PA prepore, leading to the formation of a cation-selective transmembrane pore. This pore facilitates the translocation of the enzymatic components of the anthrax toxin (edema factor and lethal factor) into the host cell cytosol, where they exert their toxic effects. ANTXR2 also acts as a molecular clamp, shifting the pH threshold for PA pore formation to more acidic ranges, thus preventing premature pore formation at neutral pH.