| Structural highlights
Function
MARTX_VIBCH Precursor of a multifunctional toxin that causes destruction of the actin cytoskeleton by covalent cross-linking of actin and inactivation of Rho GTPases when translocated into the host cytoplasm (PubMed:26185092). Upon translocation into the host cell, undergoes autoprocessing in cis mediated by the peptidase C80 domain (also named CPD domain): the protease activity is activated upon binding inositol hexakisphosphate (InsP6) present at the host cell membrane and delivers the Cysteine protease domain-containing toxin F3 chain to the host cytosol (PubMed:17464284, PubMed:18591243, PubMed:18845756, PubMed:19620709, PubMed:19465933). The Cysteine protease domain-containing toxin F3 chain will then further cleave and release effector toxin chains that cause disassembly of the actin cytoskeleton and enhance V.cholerae colonization of the small intestine, possibly by facilitating evasion of phagocytic cells (PubMed:11553575, PubMed:12045243, PubMed:17698573, PubMed:17698571, PubMed:19812690, PubMed:19620709).[1] [2] [3] [4] [5] [6] [7] [8] [9] Following autocatalytic cleavage in cis at the Leu-3441-Ala-3442 site, this chain mediates processing in trans to release other individual toxin chains to the host cytosol (PubMed:19620709). Released effector toxin chains cause disassembly of the actin cytoskeleton and enhance V.cholerae colonization of the small intestine, possibly by facilitating evasion of phagocytic cells (PubMed:17698573, PubMed:17698571).[10] [11] [12] Actin-directed toxin that catalyzes the covalent cross-linking of host cytoplasmic monomeric actin (PubMed:11032799, PubMed:15199181, PubMed:16954226, PubMed:17951576, PubMed:19015515, PubMed:19656298, PubMed:23029200, PubMed:26228148). Mediates the cross-link between 'Lys-50' of one monomer and 'Glu-270' of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148). Acts as an acid--amino-acid ligase that transfers the gamma-phosphoryl group of ATP to the 'Glu-270' actin residue, resulting in the formation of an activated acyl phosphate intermediate. This intermediate is further hydrolyzed and the energy of hydrolysis is utilized for the formation of the amide bond between actin subunits (PubMed:23029200).[13] [14] [15] [16] [17] [18] [19] [20] Actin-directed toxin that catalyzes the covalent cross-linking of host cytoplasmic monomeric actin (PubMed:11032799, PubMed:15199181, PubMed:16954226, PubMed:17951576, PubMed:19015515, PubMed:19656298, PubMed:23029200, PubMed:26228148). Mediates the cross-link between 'Lys-50' of one monomer and 'Glu-270' of another actin monomer, resulting in formation of highly toxic actin oligomers that cause cell rounding (PubMed:19015515). The toxin can be highly efficient at very low concentrations by acting on formin homology family proteins: toxic actin oligomers bind with high affinity to formins and adversely affect both nucleation and elongation abilities of formins, causing their potent inhibition in both profilin-dependent and independent manners (PubMed:26228148). Acts as an acid--amino-acid ligase that transfers the gamma-phosphoryl group of ATP to the 'Glu-270' actin residue, resulting in the formation of an activated acyl phosphate intermediate. This intermediate is further hydrolyzed and the energy of hydrolysis is utilized for the formation of the amide bond between actin subunits (PubMed:23029200).[21] [22] [23] [24] [25] [26] [27] [28] N-epsilon-fatty acyltransferase that mediates lysine-palmitoylation of host Rho GTPase proteins, with a strong preference for host Rac1 (PubMed:29074776). After delivery to the host cytosol, localizes to the host cell membrane where it palmitoylates host Rho GTPase proteins, resulting in loss of all active GTP-bound Rho and subsequent actin depolymerization (PubMed:17474905, PubMed:19434753, PubMed:23184949, PubMed:29074776). Prenylation of host Rac1 at the C-terminus is required for lysine-palmitoylation (PubMed:29074776).[29] [30] [31] [32] Indirectly activates the small GTPase CDC42.[33]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The multifunctional autoprocessing repeats-in-toxin (MARTX) toxin of Vibrio cholerae causes destruction of the actin cytoskeleton by covalent cross-linking of actin and inactivation of Rho GTPases. The effector domains responsible for these activities are here shown to be independent proteins released from the large toxin by autoproteolysis catalyzed by an embedded cysteine protease domain (CPD). The CPD is activated upon binding inositol hexakisphosphate (InsP(6)). In this study, we demonstrated that InsP(6) is not simply an allosteric cofactor, but rather binding of InsP(6) stabilized the CPD structure, facilitating formation of the enzyme-substrate complex. The 1.95-A crystal structure of this InsP(6)-bound unprocessed form of CPD was determined and revealed the scissile bond Leu(3428)-Ala(3429) captured in the catalytic site. Upon processing at this site, CPD was converted to a form with 500-fold reduced affinity for InsP(6), but was reactivated for high affinity binding of InsP(6) by cooperative binding of both a new substrate and InsP(6). Reactivation of CPD allowed cleavage of the MARTX toxin at other sites, specifically at leucine residues between the effector domains. Processed CPD also cleaved other proteins in trans, including the leucine-rich protein YopM, demonstrating that it is a promiscuous leucine-specific protease.
Structural and molecular mechanism for autoprocessing of MARTX toxin of Vibrio cholerae at multiple sites.,Prochazkova K, Shuvalova LA, Minasov G, Voburka Z, Anderson WF, Satchell KJ J Biol Chem. 2009 Sep 25;284(39):26557-68. Epub 2009 Jul 20. PMID:19620709[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fullner KJ, Lencer WI, Mekalanos JJ. Vibrio cholerae-induced cellular responses of polarized T84 intestinal epithelial cells are dependent on production of cholera toxin and the RTX toxin. Infect Immun. 2001 Oct;69(10):6310-7. PMID:11553575 doi:10.1128/IAI.69.10.6310-6317.2001
- ↑ Fullner KJ, Boucher JC, Hanes MA, Haines GK 3rd, Meehan BM, Walchle C, Sansonetti PJ, Mekalanos JJ. The contribution of accessory toxins of Vibrio cholerae O1 El Tor to the proinflammatory response in a murine pulmonary cholera model. J Exp Med. 2002 Jun 3;195(11):1455-62. PMID:12045243 doi:10.1084/jem.20020318
- ↑ Sheahan KL, Cordero CL, Satchell KJ. Autoprocessing of the Vibrio cholerae RTX toxin by the cysteine protease domain. EMBO J. 2007 May 16;26(10):2552-61. PMID:17464284 doi:10.1038/sj.emboj.7601700
- ↑ Prochazkova K, Satchell KJ. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing of the Vibrio cholerae multifunctional autoprocessing RTX toxin. J Biol Chem. 2008 Aug 29;283(35):23656-64. PMID:18591243 doi:10.1074/jbc.M803334200
- ↑ Lupardus PJ, Shen A, Bogyo M, Garcia KC. Small molecule-induced allosteric activation of the Vibrio cholerae RTX cysteine protease domain. Science. 2008 Oct 10;322(5899):265-8. PMID:18845756 doi:322/5899/265
- ↑ Shen A, Lupardus PJ, Albrow VE, Guzzetta A, Powers JC, Garcia KC, Bogyo M. Mechanistic and structural insights into the proteolytic activation of Vibrio cholerae MARTX toxin. Nat Chem Biol. 2009 Jul;5(7):469-78. PMID:19465933 doi:10.1038/nchembio.178
- ↑ Prochazkova K, Shuvalova LA, Minasov G, Voburka Z, Anderson WF, Satchell KJ. Structural and molecular mechanism for autoprocessing of MARTX toxin of Vibrio cholerae at multiple sites. J Biol Chem. 2009 Sep 25;284(39):26557-68. Epub 2009 Jul 20. PMID:19620709 doi:10.1074/jbc.M109.025510
- ↑ Olivier V, Queen J, Satchell KJ. Successful small intestine colonization of adult mice by Vibrio cholerae requires ketamine anesthesia and accessory toxins. PLoS One. 2009 Oct 8;4(10):e7352. PMID:19812690 doi:10.1371/journal.pone.0007352
- ↑ Satchell KJF. Multifunctional-autoprocessing repeats-in-toxin (MARTX) Toxins of Vibrios. Microbiol Spectr. 2015 Jun;3(3):10.1128/microbiolspec.VE-0002-2014. PMID:26185092 doi:10.1128/microbiolspec.VE-0002-2014
- ↑ Olivier V, Salzman NH, Satchell KJ. Prolonged colonization of mice by Vibrio cholerae El Tor O1 depends on accessory toxins. Infect Immun. 2007 Oct;75(10):5043-51. PMID:17698571 doi:10.1128/IAI.00508-07
- ↑ Olivier V, Haines GK 3rd, Tan Y, Satchell KJ. Hemolysin and the multifunctional autoprocessing RTX toxin are virulence factors during intestinal infection of mice with Vibrio cholerae El Tor O1 strains. Infect Immun. 2007 Oct;75(10):5035-42. PMID:17698573 doi:10.1128/IAI.00506-07
- ↑ Prochazkova K, Shuvalova LA, Minasov G, Voburka Z, Anderson WF, Satchell KJ. Structural and molecular mechanism for autoprocessing of MARTX toxin of Vibrio cholerae at multiple sites. J Biol Chem. 2009 Sep 25;284(39):26557-68. Epub 2009 Jul 20. PMID:19620709 doi:10.1074/jbc.M109.025510
- ↑ Fullner KJ, Mekalanos JJ. In vivo covalent cross-linking of cellular actin by the Vibrio cholerae RTX toxin. EMBO J. 2000 Oct 16;19(20):5315-23. PMID:11032799 doi:10.1093/emboj/19.20.5315
- ↑ Sheahan KL, Cordero CL, Satchell KJ. Identification of a domain within the multifunctional Vibrio cholerae RTX toxin that covalently cross-links actin. Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9798-803. PMID:15199181 doi:10.1073/pnas.0401104101
- ↑ Cordero CL, Kudryashov DS, Reisler E, Satchell KJ. The Actin cross-linking domain of the Vibrio cholerae RTX toxin directly catalyzes the covalent cross-linking of actin. J Biol Chem. 2006 Oct 27;281(43):32366-74. PMID:16954226 doi:10.1074/jbc.M605275200
- ↑ Kudryashov DS, Cordero CL, Reisler E, Satchell KJF. Characterization of the enzymatic activity of the actin cross-linking domain from the Vibrio cholerae MARTX Vc toxin. J Biol Chem. 2008 Jan 4;283(1):445-452. PMID:17951576 doi:10.1074/jbc.M703910200
- ↑ Kudryashov DS, Durer ZA, Ytterberg AJ, Sawaya MR, Pashkov I, Prochazkova K, Yeates TO, Loo RR, Loo JA, Satchell KJ, Reisler E. Connecting actin monomers by iso-peptide bond is a toxicity mechanism of the Vibrio cholerae MARTX toxin. Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18537-42. Epub 2008 Nov 17. PMID:19015515
- ↑ Geissler B, Bonebrake A, Sheahan KL, Walker ME, Satchell KJ. Genetic determination of essential residues of the Vibrio cholerae actin cross-linking domain reveals functional similarity with glutamine synthetases. Mol Microbiol. 2009 Sep;73(5):858-68. PMID:19656298 doi:10.1111/j.1365-2958.2009.06810.x
- ↑ Kudryashova E, Kalda C, Kudryashov DS. Glutamyl phosphate is an activated intermediate in actin crosslinking by actin crosslinking domain (ACD) toxin. PLoS One. 2012;7(9):e45721. PMID:23029200 doi:10.1371/journal.pone.0045721
- ↑ Heisler DB, Kudryashova E, Grinevich DO, Suarez C, Winkelman JD, Birukov KG, Kotha SR, Parinandi NL, Vavylonis D, Kovar DR, Kudryashov DS. ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization. Science. 2015 Jul 31;349(6247):535-9. PMID:26228148 doi:10.1126/science.aab4090
- ↑ Fullner KJ, Mekalanos JJ. In vivo covalent cross-linking of cellular actin by the Vibrio cholerae RTX toxin. EMBO J. 2000 Oct 16;19(20):5315-23. PMID:11032799 doi:10.1093/emboj/19.20.5315
- ↑ Sheahan KL, Cordero CL, Satchell KJ. Identification of a domain within the multifunctional Vibrio cholerae RTX toxin that covalently cross-links actin. Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9798-803. PMID:15199181 doi:10.1073/pnas.0401104101
- ↑ Cordero CL, Kudryashov DS, Reisler E, Satchell KJ. The Actin cross-linking domain of the Vibrio cholerae RTX toxin directly catalyzes the covalent cross-linking of actin. J Biol Chem. 2006 Oct 27;281(43):32366-74. PMID:16954226 doi:10.1074/jbc.M605275200
- ↑ Kudryashov DS, Cordero CL, Reisler E, Satchell KJF. Characterization of the enzymatic activity of the actin cross-linking domain from the Vibrio cholerae MARTX Vc toxin. J Biol Chem. 2008 Jan 4;283(1):445-452. PMID:17951576 doi:10.1074/jbc.M703910200
- ↑ Kudryashov DS, Durer ZA, Ytterberg AJ, Sawaya MR, Pashkov I, Prochazkova K, Yeates TO, Loo RR, Loo JA, Satchell KJ, Reisler E. Connecting actin monomers by iso-peptide bond is a toxicity mechanism of the Vibrio cholerae MARTX toxin. Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18537-42. Epub 2008 Nov 17. PMID:19015515
- ↑ Geissler B, Bonebrake A, Sheahan KL, Walker ME, Satchell KJ. Genetic determination of essential residues of the Vibrio cholerae actin cross-linking domain reveals functional similarity with glutamine synthetases. Mol Microbiol. 2009 Sep;73(5):858-68. PMID:19656298 doi:10.1111/j.1365-2958.2009.06810.x
- ↑ Kudryashova E, Kalda C, Kudryashov DS. Glutamyl phosphate is an activated intermediate in actin crosslinking by actin crosslinking domain (ACD) toxin. PLoS One. 2012;7(9):e45721. PMID:23029200 doi:10.1371/journal.pone.0045721
- ↑ Heisler DB, Kudryashova E, Grinevich DO, Suarez C, Winkelman JD, Birukov KG, Kotha SR, Parinandi NL, Vavylonis D, Kovar DR, Kudryashov DS. ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization. Science. 2015 Jul 31;349(6247):535-9. PMID:26228148 doi:10.1126/science.aab4090
- ↑ Sheahan KL, Satchell KJ. Inactivation of small Rho GTPases by the multifunctional RTX toxin from Vibrio cholerae. Cell Microbiol. 2007 May;9(5):1324-35. PMID:17474905 doi:10.1111/j.1462-5822.2006.00876.x
- ↑ Pei J, Grishin NV. The Rho GTPase inactivation domain in Vibrio cholerae MARTX toxin has a circularly permuted papain-like thiol protease fold. Proteins. 2009 Nov 1;77(2):413-9. PMID:19434753 doi:10.1002/prot.22447
- ↑ Ahrens S, Geissler B, Satchell KJ. Identification of a His-Asp-Cys catalytic triad essential for function of the Rho inactivation domain (RID) of Vibrio cholerae MARTX toxin. J Biol Chem. 2013 Jan 11;288(2):1397-408. PMID:23184949 doi:10.1074/jbc.M112.396309
- ↑ Zhou Y, Huang C, Yin L, Wan M, Wang X, Li L, Liu Y, Wang Z, Fu P, Zhang N, Chen S, Liu X, Shao F, Zhu Y. N(ε)-Fatty acylation of Rho GTPases by a MARTX toxin effector. Science. 2017 Oct 27;358(6362):528-531. PMID:29074776 doi:10.1126/science.aam8659
- ↑ Dolores JS, Agarwal S, Egerer M, Satchell KJ. Vibrio cholerae MARTX toxin heterologous translocation of beta-lactamase and roles of individual effector domains on cytoskeleton dynamics. Mol Microbiol. 2015 Feb;95(4):590-604. PMID:25427654 doi:10.1111/mmi.12879
- ↑ Prochazkova K, Shuvalova LA, Minasov G, Voburka Z, Anderson WF, Satchell KJ. Structural and molecular mechanism for autoprocessing of MARTX toxin of Vibrio cholerae at multiple sites. J Biol Chem. 2009 Sep 25;284(39):26557-68. Epub 2009 Jul 20. PMID:19620709 doi:10.1074/jbc.M109.025510
|
