Anthrax toxin secreted by Bacillus anthracis, consists of three polypeptides: protective antigen (PA, 83kD) lethal factor (LF, 90kD) and oedma factor (OF, 89kD). The two components (OF and LF) of the toxin enzymatically modify substrates within the cytosol of the mammalian cells: The OF is an adenylate cyclase that impairs the host defenses through a variety of mechanisms inhibiting phagocytosis. The LF is a zinc dependent protease that cleaves mitogen activated protein kinase kinase (MAPKK) and causes lysis of macrophages. To intoxicate mammalian cells, the third component of the toxin PA, binds to a ubiquitously expressed cellular receptor, Tumor Endothelium Marker-8 (TEM8). Upon binding to TEM8, PA is cleaved into 20 and 63kDa fragments (PA20 and PA63) by furin or furin-like proteases. PA63 fragment then forms a complex with LF and OF components of toxin leading to internalization and translocation of LF and OF into cytosol of the cells.
PA receptor TEM8 (also known as Anthrax Toxin receptor, ATR1) (human 564aa, mouse 562aa) is a glycoprotein with an extracellular (1-321aa), cytosolic (343-564aa) and TM (322-342) domains. The cytosolic domain is not required for translocation of LF into cytosol. The ATR/TEM8 gene is mapped at chromosome 4. Three splice variants (ATR1, ATR2 and ATR3) of TEM8/ATR have been reported. ATR1 (564aa) is the largest isoform whereas ATR2 (368aa) and ATR3 (333aa) are proteins truncated after the TM domain. The seqs (1-364aa) of ATR2 and ATR1 are identical whereas ATR3 has a unique 15aa seq at its C-terminal. ATR/TEM8 protein is expressed in a variety of cell lines and in heart, lung, lymphocytes and in central nervous system. The fact that Von Willebrand Factor Type A domain (VWA) (44-216aa) present in ATR