1.C.4 The Aerolysin Channel-forming Toxin (Aerolysin) Family

The aerolysins are a closely related group of channel-forming toxins secreted by members of the family Aeromonas, important human and animal pathogens. They are activated by host and bacterial proteases which remove a C-terminal fragment of about 40 amino acyl residues. The activated monomeric toxin then binds to a receptor glycosyl phosphatidylinositol (GPI)-anchored protein on the surface of the target cell. Because GPI anchored proteins are incorporated into the envelope membrane of human immunodeficiency virus type I (HIV-1), aerolysin can neutralize the virus in a process that depends on channel formation. The dual chaperone role of the C-terminal propeptide of aerolysin participates in folding and oligomerization of the pore-forming toxin (Iacovache et al., 2011). Monomer activation is possibly the rate-limiting step for the entire pore formation process, probably through release of a propeptide (Bischofberger et al. 2016). A loop that lines the aerolysin channel has an alternating pattern of charged and uncharged residues, suggesting that this transmembrane region has a beta-barrel configuration, as observed for Staphylococcal alpha-toxin. The turn of the beta-hairpin is composed of a stretch of five hydrophobic residues which drives membrane insertion of the developing channel. Possibly once the lipid bilayer has been crossed, it folds back parallel to the plane of the membrane in a rivet-like fashion (Iacovache et al. 2006).

Aerolysin-like pore-forming proteins are characterized by a domain organization and mechanism of action that involves extensive conformational rearrangements. The structures of the membrane integraed pores, well-defined beta-barrels, and their mechanism of assembly are fairly well understood (Podobnik et al. 2017). The cell surface-binding domains present high variability within the family to provide membrane receptor specificity (Cirauqui et al. 2017). However, the novel concentric double β-barrel structure found in aerolysin is highly conserved in terms of sequence, structure and conformational dynamics, which likely contribute to preserve a common transition mechanism from the prepore to the mature pore within the family. The key role of several amino acids in the conformational changes needed for oligomerization and further pore formation, include Y221, W227, P248, Q263 and L277, which may be involved in the release of the stem loop and the two adjacent β-strands to form the transmembrane β-barrel (Cirauqui et al. 2017).

Membrane binding of the monomeric toxin promotes oligomerization to a stable heptamer (as is known for the homologous α-hemolysin (αHL) family (TC #1.C.3)). Heptamerization converts the protein from a soluble form to a membrane insertion-competent form, and the oligomer penetrates the membrane producing channels that destroy the permeability barrier of the membrane, thereby killing the cell. The membrane-associated channel-forming protein may comprise a β-barrel. The three-dimensional structure of the soluble form of aerolysin from the Gram-negative bacterium, Aeromonas hydrophila, has been determined by x-ray crystallography (2.8 Å resolution) (Parker et al., 1994, 1996). The closely related aerolysins are distantly related to many other toxins including the α-toxin of the Gram-positive bacterium, Clostridium septicum, enterolobin, a cytolysin of the plant, Enterolobium contortisiliquum, the ε-toxin of Clostridium perfringens (1.C.5.1.1), and the α-hemolysin of Staphylococcus aureus (1.C.3.1.1). Members of the aerolysin family are therefore found in both bacteria and eukaryotes.

Hydralysins (1.C.4.2.1) are β pore-forming toxins in cnidaria, venomous animals such as Hydra vulgaris, and Chlorohydra viridissima (Sher et al., 2005). The soluble monomers are rich in β-structure and bind to erythrocyte membranes to form pores with an inner diameter of about 1.2 nm (Sher et al., 2005). Cytolysis is cell type-specific, suggesting the involvement of specific receptors. These toxins share some motif similarity around the pore-forming domains of the toxins. They induce immediate fast muscle contraction followed by flaccid paralysis when injected into blowfly larvae (Zhang et al., 2003). They have strong hemolytic activity against certain insect cells. Other toxins, including the pore-forming actinoporins, but not hydralysins, are stored in sting cells called nematocytes.

The binary toxin (Bin), produced by Lysinibacillus (Bacillus) sphaericus, is composed of BinA (42 kDa) and BinB (51 kDa) proteins, which are both required for full toxicity against Culex and Anopheles mosquito larvae. Specificity of Bin toxin is determined by the binding of BinB to a receptor present on the midgut epithelial membranes, while BinA is proposed to be a toxic component. Srisucharitpanit et al. 2014 determined the crystal structure of the active form of BinB at a resolution of 1.75 A. It possesses two distinct structural domains in its N- and C-termini. The globular N-terminal domain has a beta-trefoil scaffold which is a highly conserved architecture of some sugar binding lectins, suggesting a role of this domain in receptor-binding. The BinB beta-rich C-terminal domain shares similar three-dimensional folding with aerolysin type beta-pore forming toxins, despite a low sequence identity. The BinB structure, therefore, is a new member of the aerolysin-like toxin family, with probably similarities in the cytolytic mechanism that takes place via pore formation.

Natterin proteins are present in the venom of the fish, Thalassophryne nattereri. Members within this group of proteins, which has a remote origin (around 400 million years ago) is spread across Eukarya, even in plants and primitive Agnathans jawless fish. These proteins have a conserved motif AGIP in the pore-forming loop involved in the transmembrane barrel insertion, They are constituents of the innate immune defense system as effector molecules activating immune cells by interacting with conserved intracellular signaling mechanisms in the hosts (Lima et al. 2021).

The interaction of PFPs with lipid membranes not only causes pore-induced membrane permeabilization but also causes extensive plasma membrane reorganization. This includes lateral rearrangement and deformation of the lipid membrane, which can lead to the disruption of target cell function and finally death (Kulma and Anderluh 2021).

 

The generalized transport reaction catalyzed by members of the aerolysin family is:

Small molecules (in)  small molecules (out)



This family belongs to the Aerolysin Superfamily.

 

References:

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Bischofberger, M., I. Iacovache, D. Boss, F. Naef, F.G. van der Goot, and N. Molina. (2016). Revealing Assembly of a Pore-Forming Complex Using Single-Cell Kinetic Analysis and Modeling. Biophys. J. 110: 1574-1581.

Chen, L.L., J. Xie, D.D. Cao, N. Jia, Y.J. Li, H. Sun, W.F. Li, B. Hu, Y. Chen, and C.Z. Zhou. (2018). The pore-forming protein Aep1 is an innate immune molecule that prevents zebrafish from bacterial infection. Dev Comp Immunol 82: 49-54.

Chooduang, S., W. Surya, J. Torres, and P. Boonserm. (2018). An aromatic cluster in Lysinibacillus sphaericus BinB involved in toxicity and proper in-membrane folding. Arch Biochem Biophys 660: 29-35. [Epub: Ahead of Print]

Cirauqui, N., L.A. Abriata, F.G. van der Goot, and M. Dal Peraro. (2017). Structural, physicochemical and dynamic features conserved within the aerolysin pore-forming toxin family. Sci Rep 7: 13932.

Cowell, S., W. Aschauer, H.J. Gruber, K.L. Nelson, and J.T. Buckley. (1997). The erythrocyte receptor for the channel-forming toxin aerolysin is a novel glycosylphosphatidylinositol-anchored protein. Mol. Microbiol. 25: 343-350.

Dang, L., P. Rougé, and E.J.M. Van Damme. (2017). Amaranthin-Like Proteins with Aerolysin Domains in Plants. Front Plant Sci 8: 1368.

Degiacomi MT., Iacovache I., Pernot L., Chami M., Kudryashev M., Stahlberg H., van der Goot FG. and Dal Peraro M. (2013). Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism. Nat Chem Biol. 9(10):623-9.

Galinier, R., J. Portela, Y. Moné, J.F. Allienne, H. Henri, S. Delbecq, G. Mitta, B. Gourbal, and D. Duval. (2013). Biomphalysin, a new β pore-forming toxin involved in Biomphalaria glabrata immune defense against Schistosoma mansoni. PLoS Pathog 9: e1003216.

Hayakawa, T., M. Miyazaki, S. Harada, M. Asakura, and T. Ide. (2020). Channel-pore cation selectivity is a major determinant of Bacillus thuringiensis Cry46Ab mosquitocidal activity. Appl. Microbiol. Biotechnol. 104: 8789-8799.

Iacovache, I., M.T. Degiacomi, L. Pernot, S. Ho, M. Schiltz, M. Dal Peraro, and F.G. van der Goot. (2011). Dual chaperone role of the C-terminal propeptide in folding and oligomerization of the pore-forming toxin aerolysin. PLoS Pathog 7: e1002135.

Iacovache, I., P. Paumard, H. Scheib, C. Lesieur, N. Sakai, S. Matile, M.W. Parker, and F.G. van der Goot. (2006). A rivet model for channel formation by aerolysin-like pore-forming toxins. EMBO. J. 25: 457-466.

Iacovache, I., S. De Carlo, N. Cirauqui, M. Dal Peraro, F.G. van der Goot, and B. Zuber. (2016). Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore-formation process. Nat Commun 7: 12062.

Imagawa, T., Y. Dohi, and Y. Higashi. (1994). Cloning, nucleotide sequence and expression of a hemolysin gene of Clostridium septicum. FEMS Microbiol. Lett. 117: 287-292.

Knapp O., Maier E., Mkaddem SB., Benz R., Bens M., Chenal A., Geny B., Vandewalle A. and Popoff MR. (2010). Clostridium septicum alpha-toxin forms pores and induces rapid cell necrosis. Toxicon. 55(1):61-72.

Kulma, M. and G. Anderluh. (2021). Beyond pore formation: reorganization of the plasma membrane induced by pore-forming proteins. Cell Mol Life Sci. [Epub: Ahead of Print]

Lima, C., G.R. Disner, M.A.P. Falcão, A.C. Seni-Silva, A.L.A. Maleski, M.M. Souza, M.C. Reis Tonello, and M. Lopes-Ferreira. (2021). The Natterin Proteins Diversity: A Review on Phylogeny, Structure, and Immune Function. Toxins (Basel) 13:.

Mancheño, J.M., H. Tateno, I.J. Goldstein, M. Martínez-Ripoll, and J.A. Hermoso. (2005). Structural analysis of the Laetiporus sulphureus hemolytic pore-forming lectin in complex with sugars. J. Biol. Chem. 280: 17251-17259.

Melton, J.A., M.W. Parker, J. Rossjohn, J.T. Buckley, and R.K. Tweten. (2004). The identification and structure of the membrane-spanning domain of the Clostridium septicum alpha toxin. J. Biol. Chem. 279: 14315-14322.

Moar, W.J., A.J. Evans, C.R. Kessenich, J.A. Baum, D.J. Bowen, T.C. Edrington, J.A. Haas, J.K. Kouadio, J.K. Roberts, A. Silvanovich, Y. Yin, B.E. Weiner, K.C. Glenn, and M.L. Odegaard. (2016). The sequence, structural, and functional diversity within a protein family and implications for specificity and safety: The case for ETX_MTX2 insecticidal proteins. J Invertebr Pathol. [Epub: Ahead of Print]

Nguyen, D.H., Z. Liao, J.T. Buckley, and J.E.K. Hildreth. (1999). The channel-forming toxin aerolysin neutralizes human immunodeficiency virus type 1. Mol. Microbiol. 33: 659-666.

Parker, M.W., F.G. van der Goot, and J.T. Buckley. (1996). Aerolysin–the ins and outs of a model channel-forming toxin. Mol. Microbiol. 19: 205-212.

Parker, M.W., J.T. Buckley, J.P. Postma, A.D. Tucker, K. Leonard, F. Pattus, and D. Tsernoglou. (1994). Structure of the Aeromonas toxin proaerolysin in its water-soluble and membrane-channel states. Nature 367: 292-295.

Podobnik, M., M. Kisovec, and G. Anderluh. (2017). Molecular mechanism of pore formation by aerolysin-like proteins. Philos Trans R Soc Lond B Biol Sci 372:.

Rawat, N., M.O. Pumphrey, S. Liu, X. Zhang, V.K. Tiwari, K. Ando, H.N. Trick, W.W. Bockus, E. Akhunov, J.A. Anderson, and B.S. Gill. (2016). Wheat Fhb1 encodes a chimeric lectin with agglutinin domains and a pore-forming toxin-like domain conferring resistance to Fusarium head blight. Nat. Genet. 48: 1576-1580.

Saier, M.H., Jr., B.H. Eng, S. Fard, J. Garg, D.A. Haggerty, W.J. Hutchinson, D.L. Jack, E.C. Lai, H.J. Liu, D.P. Nusinew, A.M. Omar, S.S. Pao, I.T. Paulsen, J.A. Quan, M. Sliwinski, T.-T. Tseng, S. Wachi, and G.B. Young. (1999). Phylogenetic characterization of novel transport protein families revealed by genome analyses. Biochim. Biophys. Acta 1422: 1-56.

Sher, D. and E. Zlotkin. (2009). A hydra with many heads: protein and polypeptide toxins from hydra and their biological roles. Toxicon 54: 1148-1161.

Sher, D., Y. Fishman, M. Zhang, M. Lebendiker, A. Gaathon, J.M. Mancheno, and E. Zlotkin. (2005). Hydralysins, a new category of β-pore-forming toxins in cnidaria. J. Biol. Chem. 280: 22847-2255.

Sher, D., Y. Fishman, N. Melamed-Book, M. Zhang, and E. Zlotkin. (2008). Osmotically driven prey disintegration in the gastrovascular cavity of the green hydra by a pore-forming protein. FASEB J. 22: 207-214.

Srisucharitpanit K., Yao M., Promdonkoy B., Chimnaronk S., Tanaka I. and Boonserm P. (2014). Crystal structure of BinB: a receptor binding component of the binary toxin from Lysinibacillus sphaericus. Proteins. 82(10):2703-12.

Surya, W., S. Chooduang, Y.K. Choong, J. Torres, and P. Boonserm. (2016). Binary Toxin Subunits of Lysinibacillus sphaericus Are Monomeric and Form Heterodimers after In Vitro Activation. PLoS One 11: e0158356.

Transue, T.R., A.K. Smith, H. Mo, I.J. Goldstein, and M.A. Saper. (1997). Structure of benzyl T-antigen disaccharide bound to Amaranthus caudatus agglutinin. Nat Struct Biol 4: 779-783.

Wang, Q., X. Bian, L. Zeng, F. Pan, L. Liu, J. Liang, L. Wang, K. Zhou, W. Lee, Y. Xiang, S. Li, M. Teng, X. Li, X. Guo, and Y. Zhang. (2020). A cellular endolysosome-modulating pore-forming protein from a toad is negatively regulated by its paralog under oxidizing conditions. J. Biol. Chem. [Epub: Ahead of Print]

Whisstock, J.C. and M.A. Dunstone. (2013). Structural biology: Torqueing about pores. Nat Chem Biol 9: 605-606.

Wu, X.J., N. Dinguirard, G. Sabat, H.D. Lui, L. Gonzalez, M. Gehring, U. Bickham-Wright, and T.P. Yoshino. (2017). Proteomic analysis of Biomphalaria glabrata plasma proteins with binding affinity to those expressed by early developing larval Schistosoma mansoni. PLoS Pathog 13: e1006081.

Yang, C., L. Xie, Y. Ma, X. Cai, G. Yue, G. Qin, M. Zhang, G. Gong, X. Chang, X. Qiu, L. Luo, and H. Chen. (2021). Study on the fungicidal mechanism of glabridin against Fusarium graminearum. Pestic Biochem Physiol 179: 104963.

Zhang, M., Y. Fishman, D. Sher, and E. Zlotkin. (2003). Hydralysin, a novel animal group-selective paralytic and cytolytic protein from a noncnidocystic origin in hydra. Biochemistry 42: 8939-8944.

Examples:

TC#NameOrganismal TypeExample
1.C.4.1.1

Aerolysin (β-hemolysin; cytolytic enterotoxin) precursor (Parker et al., 1994).  Upon transition  from the prepore to pore, the aerolysin heptamer shows a unique concerted swirling movement, accompanied by a vertical collapse of the complex, ultimately leading to the insertion of a transmembrane beta-barrel (Degiacomi et al. 2013).  Multiple conformational states lead to rotation of the core lysin to unleash the membrane spanning regions (Whisstock and Dunstone 2013).  Monomer activation, dependent on proteolysis, is the rate-limiting step for pore formation (Bischofberger et al. 2016). Cryo-electron microscopy structures of three conformational intermediates and the final aerolysin pore provide insight into the conformational changes that allow pore formation. The structures reveal a protein fold consisting of two concentric beta-barrels, tightly kept together by hydrophobic interactions. This fold suggests a basis for the prion-like ultrastability of aerolysin pore and its stoichiometry (Iacovache et al. 2016).

Gram-negative bacteria of the Aeromonas family

Aerolysin precursor of Aeromonas hydrophila

 
Examples:

TC#NameOrganismal TypeExample
1.C.4.2.1

α-Toxin forms large ion permeable (slightly anion-selective) pores with no lipid specificity. It induces rapid cell necrosis in many cell types (Knapp et al., 2009). The structure of the membrane-spanning domain has been solved (Melton et al. 2004).

Gram-positive bacteria

α-toxin of Clostridium septicum (BAC54147)

 
1.C.4.2.2

A β-pore-forming cytolysin, Biomphalysin of 572 aas. It is involved in Biomphalaria glabrata immune defense against Schistosoma mansoni (Galinier et al. 2013).  Its binding properties have been studied (Wu et al. 2017).

Biomphalysin of Biomphalaria glabrata (Bloodfluke planorb) (Freshwater snail)

 
Examples:

TC#NameOrganismal TypeExample
1.C.4.3.1Enterolobin Plants Enterolobin of Enterolobium contortisiliquum (A57982)
 
Examples:

TC#NameOrganismal TypeExample
1.C.4.4.1

Hydralysin (Sher et al., 2005; Zhang et al., 2003).  Hydrolysins comprise a family of pore-forming proteins that are secreted into the gastrovascular cavity during feeding, probably helping in disintegration of the prey (Sher and Zlotkin 2009). Induces an immediate fast muscle contraction followed by flaccid paralysis when injected into blowfly larvae. The paralytic effect is lower in mice and fish. Has strong cytolytic activity against insect Sf9 cells and human HeLa cells. Binds to erythrocyte membranes and has weak hemolytic activity by mediating oligomerization and pore formation (Zhang et al. 2003; Sher et al. 2008).

Animals

Hydralysin of Hydra viridis (Q86LR2)

 
1.C.4.4.2

Spherulin 2A

Acellular slime moldsSpherulin 2A of Physarum polycephalum (P09352)
 
1.C.4.4.3

Hemolytic lectin LSLc exhibits hemolytic and hemagglutinating activities. The structure at 2.6 Å resolution has been determined (Mancheño et al., 2005). The protein is hexameric. The monomer (35kDa) consists of two distinct modules: an N-terminal lectin module (a β-trefoil scaffold) and a pore-forming module (composed of domains 2 and 4) which resemble the β-pore-forming domains of aerolysin and ε-toxin (Mancheño et al., 2005).

Fungi

LSLc of Laetiporus sulphureus (BAC78490)

 
1.C.4.4.4

Parasporin-2 β-toxin (crystal structures are known) (Akiba et al., 2009; Akiba and Okumura 2016).

Bacteria

Paraspora-2 of Bacillus thuringiensis (Q7WZI1)

 
1.C.4.4.5

Mosquitocidal toxin [synthetic construct] of 304 aas; 84% identical to 1.C.4.4.4.  Cry46Ab from Bacillus thuringiensis TK-E6 is a mosquitocidal toxin with an aerolysin-type architecture (Hayakawa et al. 2020). Cry46Ab mutants were constructed by targeting the putative transmembrane beta-hairpin region showing that charged residues within the beta-hairpin control the flux of ions through channel pores and that channel-pore cation selectivity is correlated with insecticidal activity (Hayakawa et al. 2020).

Cry4Ab Toxin, synthetic construct

 
Examples:

TC#NameOrganismal TypeExample
1.C.4.5.1The pore forming toxin-like protein, Hfr-2PlantsHfr-2 of Triticum aestivum (bread wheat) (AAW48295)
 
1.C.4.5.2

Fhb1 protein (PFT gene product) of 478 aas with two agglutinin domains followed by a DON (ETX/MTX2) domain that has the toxin activity (Rawat et al. 2016).  Counteracts Fusarium head blight (FHB), caused by Fusarium graminearum, a devastating disease of wheat and barley. The fungicidal mechanism of glabridin, an isoflavane, a type of isoflavonoid, against Fusarium graminearum, showed that it acts on ergosterol synthesis-related proteins to destroy the integrity of the cell membrane, resulting in abnormal transmembrane transport and an increased membrane potential (Yang et al. 2021).

Fhb1 of Triticum aestivum

 
1.C.4.5.3

Amaranthin agglutinin of 304 aas and 0 TMSs. The x-ray structure at 2.2 Å resolution of the homodimeric protein is available (1JLX) (Transue et al. 1997) Sequences containing amaranthin domains are widely distributed in plants (Dang et al. 2017).

Amaranthin agglutinin of Amaranthus caudatus (Love-lies-bleeding) (Inca-wheat)

 
Examples:

TC#NameOrganismal TypeExample
1.C.4.6.1

Natterin-3 precursor (venom gland protein) of 364 aas and 1 N-terminal TMS possibly plus 1 - 3 semi-hydrophobic TMSs.  See family description for details about the Natterin family (Lima et al. 2021).

Animals

Natterin-3 precursor of Thalassophryne nattereri (AAU11824)

 
1.C.4.6.2

Natterin-like precursor of 315 aas from zebra fish, Dln1 or Aep1.  Aep1 is an innate immune molecule that prevents zebrafish from bacterial infections. Thus, Aep1 may be a pro-inflammatory protein that triggers the antimicrobial immune responses (Chen et al. 2018).

Animals

Natterin-like protein of Danio rerio

 
Examples:

TC#NameOrganismal TypeExample
1.C.4.7.1

The Bin binary toxin, BinAB.  BinA is a toxic P42 protein (protein of 42 KDa) of 362 aas.  The 3-d structure of BinB (448 aas; 1.75 Å resolution) is available; it has two domains, an N-terminal sugar-binding lectin-like domain, and a C-terminal aerolysin-like β-barrel pore-forming domain. Although it shows low sequence identity with other members of the family, it is a member of the Aerolysin Family (Srisucharitpanit et al. 2014).  Protoxin subunits only form monomers, but in vitro activated toxin forms heterodimers. Maximal toxicity to mosquito larvae is achieved when the two subunits, BinA and BinB, are in a 1:1 molar ratio (Surya et al. 2016). An aromatic residue cluster in the C-terminal domain of BinB is critical for toxin insertion in membranes (Chooduang et al. 2018).

Firmicutes

BinAB of Lysinibacillus (Bacillus) sphaericus
BinA (P81935)
BinB (P10565)

 
1.C.4.7.2

Cry35 of 385 aas.  Shares a common strucure with ε-toxin, ETX (Moar et al. 2016).

Cry35 of Bacillus thuringiensis

 
Examples:

TC#NameOrganismal TypeExample
1.C.4.8.1

Cellular endolysosome-modulating aerolysin-like pore-forming protein, ALP1, of 156 aas (Wang et al. 2020). The protein shows sequence similarity in its N-terminal half with family 1.C.73 members and in its C-terminal half with family 1.C.4 members. βγ-CAT is a complex of an ALP (BmALP1) and a trefoil factor (BmTFF3) in the firebelly toad (Bombina maxima). It is a secreted endogenous pore-forming protein that modulates the biochemical properties of endolysosomes by inducing pore formation. BmALP3, a paralog of BmALP1 that lacks membrane pore-forming capacity, like BmALP1, has a conserved cysteine in its C-terminal regions. BmALP3 is readily oxidized to a disulfide bond-linked homodimer, and this homodimer can oxidize BmALP1 via disulfide bond exchange, resulting in the dissociation of βγ-CAT subunits and elimination of its biological activity. BmALP3 senses environmental oxygen tension in vivo, leading to modulation of βγ-CAT activity. This C-terminal cysteine site is well conserved in numerous vertebrate ALPs, suggesting that it is a regulatory ALP (BmALP3) that modulates the activity on the active ALP (BmALP1) in a redox-dependent manner (Wang et al. 2020).

ALP of Bombina maxima (firebelly toad)

 
1.C.4.8.2

Epidermal differentiation-specific protein, EDP, of 335 aas.

EDP of Cynops pyrrhogaster (Japanese firebelly newt)

 
1.C.4.8.3

Epidermal differentiation-specific protein-like, EDP-L, of 341 aas.

EDP-L of Erpetoichthys calabaricus (reedfish)

 
1.C.4.8.4

Epidermal differentiation-specific protein, EDP, of 406 aas.

EDP of Bagarius yarrelli (goonch)