Light Chain Diversity Among the Botulinum Neurotoxins

Overview

Journal Toxins (Basel)

Publisher MDPI

Specialty Toxicology

Date 2018 Jul 14

PMID 30004421

Citations 15

Authors

Alexander P Gardner

Joseph T Barbieri

Affiliations

Soon will be listed here.

Abstract

Botulinum neurotoxins (BoNT) are produced by several species of clostridium. There are seven immunologically unique BoNT serotypes (A⁻G). The Centers for Disease Control classifies BoNTs as 'Category A' select agents and are the most lethal protein toxins for humans. Recently, BoNT-like proteins have also been identified in several non-clostridia. BoNTs are di-chain proteins comprised of an -terminal zinc metalloprotease Light Chain (LC) and a C-terminal Heavy Chain (HC) which includes the translocation and receptor binding domains. The two chains are held together by a disulfide bond. The LC cleaves Soluble -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). The cleavage of SNAREs inhibits the fusion of synaptic vesicles to the cell membrane and the subsequent release of acetylcholine, which results in flaccid paralysis. The LC controls the catalytic properties and the duration of BoNT action. This review discusses the mechanism for LC catalysis, LC translocation, and the basis for the duration of LC action. Understanding these properties of the LC may expand the applications of BoNT as human therapies.

Citing Articles

Embracing the Versatility of Botulinum Neurotoxins in Conventional and New Therapeutic Applications.

Rasetti-Escargueil C, Palea S Toxins (Basel). 2024; 16(6).

PMID: 38922155 PMC: 11209287. DOI: 10.3390/toxins16060261.

A DARPin promotes faster onset of botulinum neurotoxin A1 action.

Leka O, Wu Y, Zanetti G, Furler S, Reinberg T, Marinho J Nat Commun. 2023; 14(1):8317.

PMID: 38110403 PMC: 10728214. DOI: 10.1038/s41467-023-44102-4.

Recent Developments in Vaccine Design: From Live Vaccines to Recombinant Toxin Vaccines.

Gupta S, Pellett S Toxins (Basel). 2023; 15(9).

PMID: 37755989 PMC: 10536331. DOI: 10.3390/toxins15090563.

Crystal Structure of the Catalytic Domain of a Botulinum Neurotoxin Homologue from : Potential Insights into Substrate Recognition.

Gregory K, Hall P, Onuh J, Mojanaga O, Liu S, Acharya K Int J Mol Sci. 2023; 24(16).

PMID: 37628902 PMC: 10454453. DOI: 10.3390/ijms241612721.

Biological and Immunological Characterization of a Functional L-HN Derivative of Botulinum Neurotoxin Serotype F.

Li Z, Li B, Lu J, Liu X, Tan X, Wang R Toxins (Basel). 2023; 15(3).

PMID: 36977091 PMC: 10056376. DOI: 10.3390/toxins15030200.

References

Yamasaki S, Hu Y, Binz T, Kalkuhl A, Kurazono H, Tamura T . Synaptobrevin/vesicle-associated membrane protein (VAMP) of Aplysia californica: structure and proteolysis by tetanus toxin and botulinal neurotoxins type D and F. Proc Natl Acad Sci U S A. 1994; 91(11):4688-92. PMC: 43853. DOI: 10.1073/pnas.91.11.4688. View

Sikorra S, Litschko C, Muller C, Thiel N, Galli T, Eichner T . Identification and Characterization of Botulinum Neurotoxin A Substrate Binding Pockets and Their Re-Engineering for Human SNAP-23. J Mol Biol. 2015; 428(2 Pt A):372-384. DOI: 10.1016/j.jmb.2015.10.024. View

Lacy D, Tepp W, Cohen A, Dasgupta B, Stevens R . Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol. 1998; 5(10):898-902. DOI: 10.1038/2338. View

Rummel A . Double receptor anchorage of botulinum neurotoxins accounts for their exquisite neurospecificity. Curr Top Microbiol Immunol. 2012; 364:61-90. DOI: 10.1007/978-3-642-33570-9_4. View

Jahn R, Scheller R . SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol. 2006; 7(9):631-43. DOI: 10.1038/nrm2002. View

Whitemarsh R, Tepp W, Bradshaw M, Lin G, Pier C, Scherf J . Characterization of botulinum neurotoxin A subtypes 1 through 5 by investigation of activities in mice, in neuronal cell cultures, and in vitro. Infect Immun. 2013; 81(10):3894-902. PMC: 3811745. DOI: 10.1128/IAI.00536-13. View

Li L, Binz T, Niemann H, Singh B . Probing the mechanistic role of glutamate residue in the zinc-binding motif of type A botulinum neurotoxin light chain. Biochemistry. 2000; 39(9):2399-405. DOI: 10.1021/bi992321x. View

Kauffman J, Way Jr J, Siegel L, Sellin L . Comparison of the action of types A and F botulinum toxin at the rat neuromuscular junction. Toxicol Appl Pharmacol. 1985; 79(2):211-7. DOI: 10.1016/0041-008x(85)90342-4. View

Schiavo G, Shone C, Rossetto O, Alexander F, Montecucco C . Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin. J Biol Chem. 1993; 268(16):11516-9. View

10.

Hackett G, Moore K, Burgin D, Hornby F, Gray B, Elliott M . Purification and Characterization of Recombinant Botulinum Neurotoxin Serotype FA, Also Known as Serotype H. Toxins (Basel). 2018; 10(5). PMC: 5983251. DOI: 10.3390/toxins10050195. View

11.

OHISHI I, Iwasaki M, Sakaguchi G . Purification and characterization of two components of botulinum C2 toxin. Infect Immun. 1980; 30(3):668-73. PMC: 551367. DOI: 10.1128/iai.30.3.668-673.1980. View

12.

Aoki K, Guyer B . Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions. Eur J Neurol. 2002; 8 Suppl 5:21-9. DOI: 10.1046/j.1468-1331.2001.00035.x. View

13.

Kalb S, Baudys J, Webb R, Wright P, Smith T, Smith L . Discovery of a novel enzymatic cleavage site for botulinum neurotoxin F5. FEBS Lett. 2011; 586(2):109-15. PMC: 3263758. DOI: 10.1016/j.febslet.2011.11.033. View

14.

Schiavo G, Rossetto O, Catsicas S, Polverino De Laureto P, Dasgupta B, Benfenati F . Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E. J Biol Chem. 1993; 268(32):23784-7. View

15.

Binz T, Blasi J, Yamasaki S, Baumeister A, Link E, Sudhof T . Proteolysis of SNAP-25 by types E and A botulinal neurotoxins. J Biol Chem. 1994; 269(3):1617-20. View

16.

Toyama B, Savas J, Park S, Harris M, Ingolia N, Yates 3rd J . Identification of long-lived proteins reveals exceptional stability of essential cellular structures. Cell. 2013; 154(5):971-982. PMC: 3788602. DOI: 10.1016/j.cell.2013.07.037. View

17.

Schiavo G, Rossetto O, Santucci A, Dasgupta B, Montecucco C . Botulinum neurotoxins are zinc proteins. J Biol Chem. 1992; 267(33):23479-83. View

18.

Sathyamoorthy V, Dasgupta B . Separation, purification, partial characterization and comparison of the heavy and light chains of botulinum neurotoxin types A, B, and E. J Biol Chem. 1985; 260(19):10461-6. View

19.

Singh B, Dasgupta B . Conformational changes associated with the nicking and activation of botulinum neurotoxin type E. Biophys Chem. 1990; 38(1-2):123-30. DOI: 10.1016/0301-4622(90)80047-b. View

20.

Cambridge S, Gnad F, Nguyen C, Lorenzo Bermejo J, Kruger M, Mann M . Systems-wide proteomic analysis in mammalian cells reveals conserved, functional protein turnover. J Proteome Res. 2011; 10(12):5275-84. DOI: 10.1021/pr101183k. View