Identification and Functional Characterization of Novel Venom Components

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 52559

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Special Issue Editor

Technical Editor, Nakama, Onna-son, Kunigami-gun, Okinawa-ken 904-0401, Japan
Interests: chemistry of animal venoms, particularly of snakes; snake envenomation strategies; contributions of individual venom components to prey immobilization; ecology of venomous animals

Special Issue Information

Dear Colleagues,

Throughout most of the 20th century, the toxinological literature consisted largely of pharmacological and functional characterizations of crude venoms and venom constituents, often constituents that could not be identified unambiguously. The advent of amino acid composition analysis in the 1950s enabled the first forays into physical characterizations of purified toxins, though these remained few in number until the 1970s. Then, tryptic and chymotryptic cleavage of venom proteins coupled with manual Edman degradation began to provide the first complete sequences, particularly of three-finger toxins. Polyacrylamide gel electrophoresis and improved resins for liquid chromatography permitted improved purification and better gross structural characterization of venom components. The early 1980s saw the advent of automated Edman degradation, and entire sequences of longer proteins began to appear in the literature. Then, the molecular biology revolution made it possible to generate cDNA sequences of more and larger proteins, followed by mass spectrometry-based proteomics and quantitative high-throughput DNA sequencing and genomics. Today, we face a hitherto unprecedented situation in which our capacity to generate sequence/structural data has completely overwhelmed our capacity to characterize venom constituents functionally.

This Special Issue of Toxins is devoted specifically to the discovery and functional characterization of novel venom constituents of vertebrate and invertebrate venoms.

Dr. Steven D. Aird
Guest Editor

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Published Papers (12 papers)

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Editorial

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3 pages, 188 KiB  
Editorial
Introduction to the Toxins Special Issue on Identification and Functional Characterization of Novel Venom Components
by Steven D. Aird
Toxins 2020, 12(5), 336; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12050336 - 20 May 2020
Cited by 1 | Viewed by 2069
Abstract
Throughout most of the 20th century, the toxinological literature consisted largely of pharmacological and functional characterizations of crude venoms and venom constituents, often constituents that could not be identified unambiguously [...] Full article

Research

Jump to: Editorial, Review

16 pages, 1200 KiB  
Article
Discovery of the Gene Encoding a Novel Small Serum Protein (SSP) of Protobothrops flavoviridis and the Evolution of SSPs
by Kento Inamaru, Ami Takeuchi, Marie Maeda, Hiroki Shibata, Yasuyuki Fukumaki, Naoko Oda-Ueda, Shosaku Hattori, Motonori Ohno and Takahito Chijiwa
Toxins 2020, 12(3), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12030177 - 12 Mar 2020
Cited by 1 | Viewed by 2198
Abstract
Small serum proteins (SSPs) are low-molecular-weight proteins in snake serum with affinities for various venom proteins. Five SSPs, PfSSP-1 through PfSSP-5, have been reported in Protobothrops flavoviridis (“habu”, Pf) serum so far. Recently, we reported that the five genes encoding [...] Read more.
Small serum proteins (SSPs) are low-molecular-weight proteins in snake serum with affinities for various venom proteins. Five SSPs, PfSSP-1 through PfSSP-5, have been reported in Protobothrops flavoviridis (“habu”, Pf) serum so far. Recently, we reported that the five genes encoding these PfSSPs are arranged in tandem on a single chromosome. However, the physiological functions and evolutionary origins of the five SSPs remain poorly understood. In a detailed analysis of the habu draft genome, we found a gene encoding a novel SSP, SSP-6. Structural analysis of the genes encoding SSPs and their genomic arrangement revealed the following: (1) SSP-6 forms a third SSP subgroup; (2) SSP-5 and SSP-6 were present in all snake genomes before the divergence of non-venomous and venomous snakes, while SSP-4 was acquired only by venomous snakes; (3) the composition of paralogous SSP genes in snake genomes seems to reflect snake habitat differences; and (4) the evolutionary emergence of SSP genes is probably related to the physiological functions of SSPs, with an initial snake repertoire of SSP-6 and SSP-5. SSP-4 and its derivative, SSP-3, as well as SSP-1 and SSP-2, appear to be venom-related and were acquired later. Full article
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20 pages, 4865 KiB  
Article
A Novel αIIbβ3 Antagonist from Snake Venom Prevents Thrombosis without Causing Bleeding
by Yu-Ju Kuo, Ching-Hu Chung, Tzu-Yu Pan, Woei-Jer Chuang and Tur-Fu Huang
Toxins 2020, 12(1), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12010011 - 21 Dec 2019
Cited by 9 | Viewed by 3080
Abstract
Life-threatening thrombocytopenia and bleeding, common side effects of clinically available αIIbβ3 antagonists, are associated with the induction of ligand-induced integrin conformational changes and exposure of ligand-induced binding sites (LIBSs). To address this issue, we examined intrinsic mechanisms and structure–activity relationships [...] Read more.
Life-threatening thrombocytopenia and bleeding, common side effects of clinically available αIIbβ3 antagonists, are associated with the induction of ligand-induced integrin conformational changes and exposure of ligand-induced binding sites (LIBSs). To address this issue, we examined intrinsic mechanisms and structure–activity relationships of purified disintegrins, from Protobothrops flavoviridis venom (i.e., Trimeresurus flavoviridis), TFV-1 and TFV-3 with distinctly different pro-hemorrhagic tendencies. TFV-1 with a different αIIbβ3 binding epitope from that of TFV-3 and chimeric 7E3 Fab, i.e., Abciximab, decelerates αIIbβ3 ligation without causing a conformational change in αIIbβ3, as determined with the LIBS antibody, AP5, and the mimetic, drug-dependent antibody (DDAb), AP2, an inhibitory monoclonal antibody raised against αIIbβ3. Consistent with their different binding epitopes, a combination of TFV-1 and AP2 did not induce FcγRIIa-mediated activation of the ITAM–Syk–PLCγ2 pathway and platelet aggregation, in contrast to the clinical antithrombotics, abciximab, eptifibatide, and disintegrin TFV-3. Furthermore, TFV-1 selectively inhibits Gα13-mediated platelet aggregation without affecting talin-driven clot firmness, which is responsible for physiological hemostatic processes. At equally efficacious antithrombotic dosages, TFV-1 caused neither severe thrombocytopenia nor bleeding in FcγRIIa-transgenic mice. Likewise, it did not induce hypocoagulation in human whole blood in the rotational thromboelastometry (ROTEM) assay used in perioperative situations. In contrast, TFV-3 and eptifibatide exhibited all of these hemostatic effects. Thus, the αIIbβ3 antagonist, TFV-1, efficaciously prevents arterial thrombosis without adversely affecting hemostasis. Full article
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16 pages, 3185 KiB  
Article
ACP-TX-I and ACP-TX-II, Two Novel Phospholipases A2 Isolated from Trans-Pecos Copperhead Agkistrodon contortrix pictigaster Venom: Biochemical and Functional Characterization
by Salomón Huancahuire-Vega, Luciana M. Hollanda, Mauricio Gomes-Heleno, Edda E. Newball-Noriega and Sergio Marangoni
Toxins 2019, 11(11), 661; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11110661 - 14 Nov 2019
Cited by 1 | Viewed by 2725
Abstract
This work reports the purification and biochemical and functional characterization of ACP-TX-I and ACP-TX-II, two phospholipases A2 (PLA2) from Agkistrodon contortrix pictigaster venom. Both PLA2s were highly purified by a single chromatographic step on a C18 reverse [...] Read more.
This work reports the purification and biochemical and functional characterization of ACP-TX-I and ACP-TX-II, two phospholipases A2 (PLA2) from Agkistrodon contortrix pictigaster venom. Both PLA2s were highly purified by a single chromatographic step on a C18 reverse phase HPLC column. Various peptide sequences from these two toxins showed similarity to those of other PLA2 toxins from viperid snake venoms. ACP-TX-I belongs to the catalytically inactive K49 PLA2 class, while ACP-TX-II is a D49 PLA2, and is enzymatically active. ACP-TX-I PLA2 is monomeric, which results in markedly diminished myotoxic and inflammatory activities when compared with dimeric K49 PLA2s, confirming the hypothesis that dimeric structure contributes heavily to the profound myotoxicity of the most active viperid K49 PLA2s. ACP-TX-II exhibits the main pharmacological actions reported for this protein family, including in vivo local myotoxicity, edema-forming activity, and in vitro cytotoxicity. ACP-TX-I PLA2 is cytotoxic to A549 lung carcinoma cells, indicating that cytotoxicity to these tumor cells does not require enzymatic activity. Full article
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14 pages, 2930 KiB  
Article
Hadrurid Scorpion Toxins: Evolutionary Conservation and Selective Pressures
by Carlos E. Santibáñez-López, Matthew R. Graham, Prashant P. Sharma, Ernesto Ortiz and Lourival D. Possani
Toxins 2019, 11(11), 637; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11110637 - 01 Nov 2019
Cited by 9 | Viewed by 8386
Abstract
Scorpion toxins are thought to have originated from ancestral housekeeping genes that underwent diversification and neofunctionalization, as a result of positive selection. Our understanding of the evolutionary origin of these peptides is hindered by the patchiness of existing taxonomic sampling. While recent studies [...] Read more.
Scorpion toxins are thought to have originated from ancestral housekeeping genes that underwent diversification and neofunctionalization, as a result of positive selection. Our understanding of the evolutionary origin of these peptides is hindered by the patchiness of existing taxonomic sampling. While recent studies have shown phylogenetic inertia in some scorpion toxins at higher systematic levels, evolutionary dynamics of toxins among closely related taxa remain unexplored. In this study, we used new and previously published transcriptomic resources to assess evolutionary relationships of closely related scorpions from the family Hadruridae and their toxins. In addition, we surveyed the incidence of scorpine-like peptides (SLP, a type of potassium channel toxin), which were previously known from 21 scorpion species. We demonstrate that scorpine-like peptides exhibit gene duplications. Our molecular analyses demonstrate that only eight sites of two SLP copies found in scorpions are evolving under positive selection, with more sites evolving under negative selection, in contrast to previous findings. These results show evolutionary conservation in toxin diversity at shallow taxonomic scale. Full article
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24 pages, 17922 KiB  
Article
The Sequence and a Three-Dimensional Structural Analysis Reveal Substrate Specificity among Snake Venom Phosphodiesterases
by Anwar Ullah, Kifayat Ullah, Hamid Ali, Christian Betzel and Shafiq ur Rehman
Toxins 2019, 11(11), 625; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11110625 - 28 Oct 2019
Cited by 14 | Viewed by 4383
Abstract
(1) Background. Snake venom phosphodiesterases (SVPDEs) are among the least studied venom enzymes. In envenomation, they display various pathological effects, including induction of hypotension, inhibition of platelet aggregation, edema, and paralysis. Until now, there have been no 3D structural studies of these enzymes, [...] Read more.
(1) Background. Snake venom phosphodiesterases (SVPDEs) are among the least studied venom enzymes. In envenomation, they display various pathological effects, including induction of hypotension, inhibition of platelet aggregation, edema, and paralysis. Until now, there have been no 3D structural studies of these enzymes, thereby preventing structure–function analysis. To enable such investigations, the present work describes the model-based structural and functional characterization of a phosphodiesterase from Crotalus adamanteus venom, named PDE_Ca. (2) Methods. The PDE_Ca structure model was produced and validated using various software (model building: I-TESSER, MODELLER 9v19, Swiss-Model, and validation tools: PROCHECK, ERRAT, Molecular Dynamic Simulation, and Verif3D). (3) Results. The proposed model of the enzyme indicates that the 3D structure of PDE_Ca comprises four domains, a somatomedin B domain, a somatomedin B-like domain, an ectonucleotide pyrophosphatase domain, and a DNA/RNA non-specific domain. Sequence and structural analyses suggest that differences in length and composition among homologous snake venom sequences may account for their differences in substrate specificity. Other properties that may influence substrate specificity are the average volume and depth of the active site cavity. (4) Conclusion. Sequence comparisons indicate that SVPDEs exhibit high sequence identity but comparatively low identity with mammalian and bacterial PDEs. Full article
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17 pages, 2731 KiB  
Article
Identification and Functional Characterization of a Novel Insecticidal Decapeptide from the Myrmicine Ant Manica rubida
by John Heep, Marisa Skaljac, Jens Grotmann, Tobias Kessel, Maximilian Seip, Henrike Schmidtberg and Andreas Vilcinskas
Toxins 2019, 11(10), 562; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11100562 - 25 Sep 2019
Cited by 19 | Viewed by 4544
Abstract
Ant venoms contain many small, linear peptides, an untapped source of bioactive peptide toxins. The control of agricultural insect pests currently depends primarily on chemical insecticides, but their intensive use damages the environment and human health, and encourages the emergence of resistant pest [...] Read more.
Ant venoms contain many small, linear peptides, an untapped source of bioactive peptide toxins. The control of agricultural insect pests currently depends primarily on chemical insecticides, but their intensive use damages the environment and human health, and encourages the emergence of resistant pest populations. This has promoted interest in animal venoms as a source of alternative, environmentally-friendly bio-insecticides. We tested the crude venom of the predatory ant, Manica rubida, and observed severe fitness costs in the parthenogenetic pea aphid (Acyrthosiphon pisum), a common agricultural pest. Therefore, we explored the M. rubida venom peptidome and identified a novel decapeptide U-MYRTX-MANr1 (NH2-IDPKVLESLV-CONH2) using a combination of Edman degradation and de novo peptide sequencing. Although this myrmicitoxin was inactive against bacteria and fungi, it reduced aphid survival and reproduction. Furthermore, both crude venom and U-MYRTX-MANr1 reversibly paralyzed injected aphids and induced a loss of body fluids. Components of M. rubida venom may act on various biological targets including ion channels and hemolymph coagulation proteins, as previously shown for other ant venom toxins. The remarkable insecticidal activity of M. rubida venom suggests it may be a promising source of additional bio-insecticide leads. Full article
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18 pages, 4041 KiB  
Article
Lebetin 2, a Snake Venom-Derived B-Type Natriuretic Peptide, Provides Immediate and Prolonged Protection against Myocardial Ischemia-Reperfusion Injury via Modulation of Post-Ischemic Inflammatory Response
by Bochra Tourki, Anais Dumesnil, Elise Belaidi, Slim Ghrir, Diane Godin-Ribuot, Naziha Marrakchi, Vincent Richard, Paul Mulder and Erij Messadi
Toxins 2019, 11(9), 524; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11090524 - 10 Sep 2019
Cited by 12 | Viewed by 3958
Abstract
Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, [...] Read more.
Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, including post-MI inflammation and fibrosis have not been defined. Here, we determined whether a single L2 injection exerts cardioprotection in IR murine models in vivo, and whether inflammatory response to ischemic injury plays a role in L2-induced effects. We quantified infarct size (IS), fibrosis, inflammation, and both endothelial cell and cardiomyocyte densities in injured myocardium and compared these values with those induced by B-type natriuretic peptide (BNP). Both L2 and BNP reduced IS, fibrosis, and inflammatory response after IR, as evidenced by decreased leukocyte and proinflammatory M1 macrophage infiltrations in the infarcted area compared to untreated animals. However, only L2 increased anti-inflammatory M2-like macrophages. L2 also induced a higher density of endothelial cells and cardiomyocytes. Our data show that L2 has strong, acute, prolonged cardioprotective effects in post-MI that are mediated, at least in part, by the modulation of the post-ischemic inflammatory response and especially, by the enhancement of M2-like macrophages, thus reducing IR-induced necrotic and fibrotic effects. Full article
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15 pages, 2491 KiB  
Article
The Dual α-Amidation System in Scorpion Venom Glands
by Gustavo Delgado-Prudencio, Lourival D. Possani, Baltazar Becerril and Ernesto Ortiz
Toxins 2019, 11(7), 425; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11070425 - 20 Jul 2019
Cited by 28 | Viewed by 4848
Abstract
Many peptides in scorpion venoms are amidated at their C-termini. This post-translational modification is paramount for the correct biological function of ion channel toxins and antimicrobial peptides, among others. The discovery of canonical amidation sequences in transcriptome-derived scorpion proproteins suggests that a conserved [...] Read more.
Many peptides in scorpion venoms are amidated at their C-termini. This post-translational modification is paramount for the correct biological function of ion channel toxins and antimicrobial peptides, among others. The discovery of canonical amidation sequences in transcriptome-derived scorpion proproteins suggests that a conserved enzymatic α-amidation system must be responsible for this modification of scorpion peptides. A transcriptomic approach was employed to identify sequences putatively encoding enzymes of the α-amidation pathway. A dual enzymatic α-amidation system was found, consisting of the membrane-anchored, bifunctional, peptidylglycine α-amidating monooxygenase (PAM) and its paralogs, soluble monofunctional peptidylglycine α-hydroxylating monooxygenase (PHMm) and peptidyl-α-hydroxyglycine α-amidating lyase (PALm). Independent genes encode these three enzymes. Amino acid residues responsible for ion coordination and enzymatic activity are conserved in these sequences, suggesting that the enzymes are functional. Potential endoproteolytic recognition sites for proprotein convertases in the PAM sequence indicate that PAM-derived soluble isoforms may also be expressed. Sequences potentially encoding proprotein convertases (PC1 and PC2), carboxypeptidase E (CPE), and other enzymes of the α-amidation pathway, were also found, confirming the presence of this pathway in scorpions. Full article
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10 pages, 2218 KiB  
Article
A Novel Bradykinin-Related Peptide, RVA-Thr6-BK, from the Skin Secretion of the Hejiang Frog; Ordorrana hejiangensis: Effects of Mammalian Isolated Smooth Muscle
by Yue Wu, Daning Shi, Xiaoling Chen, Lei Wang, Yuan Ying, Chengbang Ma, Xinping Xi, Mei Zhou, Tianbao Chen and Chris Shaw
Toxins 2019, 11(7), 376; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11070376 - 28 Jun 2019
Cited by 5 | Viewed by 2928
Abstract
A novel naturally-occurring bradykinin-related peptide (BRP) with an N-terminal extension, named RVA-Thr6-Bradykinin (RVA-Thr6-BK), was here isolated and identified from the cutaneous secretion of Odorrana hejiangensis (O. hejiangensis). Thereafter, in order to evaluate the difference in myotropic actions, a [...] Read more.
A novel naturally-occurring bradykinin-related peptide (BRP) with an N-terminal extension, named RVA-Thr6-Bradykinin (RVA-Thr6-BK), was here isolated and identified from the cutaneous secretion of Odorrana hejiangensis (O. hejiangensis). Thereafter, in order to evaluate the difference in myotropic actions, a leucine site-substitution variant from Amolops wuyiensis skin secretion, RVA-Leu1, Thr6-BK, was chemically synthesized. Myotropic studies indicated that single-site arginine (R) replacement by leucine (L) at position-4 from the N-terminus, altered the action of RVA-Thr6-BK from an agonist to an antagonist of BK actions on rat ileum smooth muscle. Additionally, both BK N-terminal extended derivatives (RVA-Thr6-BK and RVA-Leu1, Thr6-BK) exerted identical myotropic actions to BK, such as increasing the frequency of contraction, contracting and relaxing the rat uterus, bladder and artery preparations, respectively. Full article
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Review

Jump to: Editorial, Research

23 pages, 4671 KiB  
Review
Hitchhiking with Nature: Snake Venom Peptides to Fight Cancer and Superbugs
by Clara Pérez-Peinado, Sira Defaus and David Andreu
Toxins 2020, 12(4), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12040255 - 15 Apr 2020
Cited by 33 | Viewed by 7285
Abstract
For decades, natural products in general and snake venoms (SV) in particular have been a rich source of bioactive compounds for drug discovery, and they remain a promising substrate for therapeutic development. Currently, a handful of SV-based drugs for diagnosis and treatment of [...] Read more.
For decades, natural products in general and snake venoms (SV) in particular have been a rich source of bioactive compounds for drug discovery, and they remain a promising substrate for therapeutic development. Currently, a handful of SV-based drugs for diagnosis and treatment of various cardiovascular disorders and blood abnormalities are on the market. Likewise, far more SV compounds and their mimetics are under investigation today for diverse therapeutic applications, including antibiotic-resistant bacteria and cancer. In this review, we analyze the state of the art regarding SV-derived compounds with therapeutic potential, focusing on the development of antimicrobial and anticancer drugs. Specifically, information about SV peptides experimentally validated or predicted to act as antimicrobial and anticancer peptides (AMPs and ACPs, respectively) has been collected and analyzed. Their principal activities both in vitro and in vivo, structures, mechanisms of action, and attempts at sequence optimization are discussed in order to highlight their potential as drug leads. Full article
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20 pages, 2252 KiB  
Review
Cysteine-Rich Secretory Proteins (CRISPs) from Venomous Snakes: An Overview of the Functional Diversity in a Large and Underappreciated Superfamily
by Takashi Tadokoro, Cassandra M. Modahl, Katsumi Maenaka and Narumi Aoki-Shioi
Toxins 2020, 12(3), 175; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12030175 - 12 Mar 2020
Cited by 47 | Viewed by 5308
Abstract
The CAP protein superfamily (Cysteine-rich secretory proteins (CRISPs), Antigen 5 (Ag5), and Pathogenesis-related 1 (PR-1) proteins) is widely distributed, but for toxinologists, snake venom CRISPs are the most familiar members. Although CRISPs are found in the majority of venoms, very few of these [...] Read more.
The CAP protein superfamily (Cysteine-rich secretory proteins (CRISPs), Antigen 5 (Ag5), and Pathogenesis-related 1 (PR-1) proteins) is widely distributed, but for toxinologists, snake venom CRISPs are the most familiar members. Although CRISPs are found in the majority of venoms, very few of these proteins have been functionally characterized, but those that have been exhibit diverse activities. Snake venom CRISPs (svCRISPs) inhibit ion channels and the growth of new blood vessels (angiogenesis). They also increase vascular permeability and promote inflammatory responses (leukocyte and neutrophil infiltration). Interestingly, CRISPs in lamprey buccal gland secretions also manifest some of these activities, suggesting an evolutionarily conserved function. As we strive to better understand the functions that CRISPs serve in venoms, it is worth considering the broad range of CRISP physiological activities throughout the animal kingdom. In this review, we summarize those activities, known crystal structures and sequence alignments, and we discuss predicted functional sites. CRISPs may not be lethal or major components of venoms, but given their almost ubiquitous occurrence in venoms and the accelerated evolution of svCRISP genes, these venom proteins are likely to have functions worth investigating. Full article
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