1.B.164. The Mycobacterial Outer Membrane Calcium Channel (CpnT) Family CpnT has a dual function in uptake of nutrients including Ca²⁺ and induction of host cell death. The N-terminal domain (NTD) forms an outer membrane channel and is used for uptake of nutrients across the outer membrane. The secreted C-terminal toxic domain (TNT) acts as a glycohydrolase, which hydrolyzes the essential cellular coenzyme NAD⁺ in the cytosol of infected macrophages, leading to necrotic host cell death. Both functions are required for survival, replication and cytotoxicity of M. tuberculosis in macrophages (Danilchanka et al. 2014; Sun et al. 2015). This pathogen relies upon CpnT for the development of multidrug resistance via gene mutation and the evolutionary development of new calcium channels (D'Elia and Weinrauch 2023).
References:
D'Elia, J.A. and L.A. Weinrauch. (2023). Gated Calcium Ion Channel and Mutation Mechanisms in Multidrug-Resistant Tuberculosis. Int J Mol Sci 24:.
Danilchanka, O., J. Sun, M. Pavlenok, C. Maueröder, A. Speer, A. Siroy, J. Marrero, C. Trujillo, D.L. Mayhew, K.S. Doornbos, L.E. Muñoz, M. Herrmann, S. Ehrt, C. Berens, and M. Niederweis. (2014). An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity. Proc. Natl. Acad. Sci. USA 111: 6750-6755.
Sun, J., A. Siroy, R.K. Lokareddy, A. Speer, K.S. Doornbos, G. Cingolani, and M. Niederweis. (2015). The tuberculosis necrotizing toxin kills macrophages by hydrolyzing NAD. Nat Struct Mol Biol 22: 672-678.
Examples:
TC#	Name	Organismal Type	Example
1.B.164.1.1	The nutrient outer membrane channel, CpnT, of 846 aas and 1 N=terminal TMS and possibly two more TMSs at about residues 220 and 270. It can be mutated to serve as a Ca2+ channel and promote cell death (D'Elia and Weinrauch 2023).		CpnT of Mycobacterium tuberculosis

1.B.164.1.2	Uncharacterized protein of 426 aas with two putative TMSs, one N-terminal and one at residues 250. Only the first domain, the outer membrane channel domain, presumably specific for nutrients, is present, not the toxin domain which is the C-terminal domain of CpnT (TC#1.B.164.1.1).		UP of Nocardia araoensis

1.B.164.1.3	Uncharacterized protein of 475 aas and 2 or possibly 3 TMSs, one at the N-terminus, one at about residue 220, and possibly a third (with less hydrophobicity) at about residue 270.		UP of Gordonia rubripertincta

1.B.164.1.4	Uncharacterized protein of 475 aas and 2 or 3 TMSs, one at the N-terminus of the protein and one or two are residues 320 - 370.		UP of Streptomyces tanashiensis

1.B.164.1.5	Uncharacterized protein of 1362 aas with 2 strongly hydrophobic putative TMSs between residues 270 and 320, followed by 4 more putative TMSs of much lower hydrophobicity between residues 340 and 430.		*UP of Microbacterium* sp. GCS4**

1.B.164.1.6	Uncharacterized protein of 496 aas and posibly 2 TMSs + several smaller hydrophobicity peaks that could be TMSs.		UP of Vibrio cholerae

1.B.164.1.7	Uncharacterized protein of 499 aas and 4 putative TMSs between residues 240 and 330.		*UP of Aeromicrobium* sp. (soil metagenome)**

1.B.164.1.8	Colicin D domain-containing protein of 453 aas and 2 TMSs between residues 160 and 320.		UP of Saccharopolyspora erythraea