Role of accelerated segment switch in exons to alter targeting (ASSET) in the molecular evolution of snake venom proteins

Doley, Robin; Mackessy, Stephen P.; Kini, R. Manjunatha

doi:10.1186/1471-2148-9-146

Cited by 56 publications

(31 citation statements)

References 84 publications

(91 reference statements)

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“…injections [212]. This higher potency of presynaptic PLA 2 toxins may suggest that evolution is favoring functional diversification of toxins [439,440,441] targeting two or more portals . Other bacterial proteins such as pertussis and anthrax which deregulate portal 5, G-protein-coupled receptor systems, cause toxicity in the range of 0.1–1 μg /kg body weight, stressing the importance of this large group of receptors portals in maintenance of cellular functions.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

Lahiani

Yavin

Lazarovici

2017

Toxins

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An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking. In this review, specific examples of different toxins are emphasized to illustrate the fundamental mechanisms of toxicity at different biochemical, molecular and cellular- levels with particular consideration for the nervous system. The target of primary action has been highlighted and operationally classified into 13 sub-categories. Selected examples of toxins were assigned to each target category, denominated as portal, and the modulation of the different portal’s signaling was featured. The first portal encompasses the plasma membrane lipid domains, which give rise to pores when challenged for example with pardaxin, a fish toxin, or is subject to degradation when enzymes of lipid metabolism such as phospholipases A2 (PLA2) or phospholipase C (PLC) act upon it. Several major portals consist of ion channels, pumps, transporters and ligand gated ionotropic receptors which many toxins act on, disturbing the intracellular ion homeostasis. Another group of portals consists of G-protein-coupled and tyrosine kinase receptors that, upon interaction with discrete toxins, alter second messengers towards pathological levels. Lastly, subcellular organelles such as mitochondria, nucleus, protein- and RNA-synthesis machineries, cytoskeletal networks and exocytic vesicles are also portals targeted and deregulated by other diverse group of toxins. A fundamental concept can be drawn from these seemingly different toxins with respect to the site of action and the secondary messengers and signaling cascades they trigger in the host. While the interaction with the initial portal is largely determined by the chemical nature of the toxin, once inside the cell, several ubiquitous second messengers and protein kinases/ phosphatases pathways are impaired, to attain toxicity. Therefore, toxins represent one of the most promising natural molecules for developing novel therapeutics that selectively target the major cellular portals involved in human physiology and diseases.

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Section: Discussionmentioning

confidence: 99%

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

Lahiani

Yavin

Lazarovici

2017

Toxins

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“…It has been hypothesized that some multi-nucleotide sequences (segments) undergo switching, leading to changes in the amino acid sequence that alters the targeting of various ion-channels/receptors. This phenomenon, initially discovered through transcriptomic analysis, has also been seen in other taxa (Doley et al, 2009). Recently Sunagar et al, have proposed a new hypothesis to explain the molecular evolution of the 3FTx gene called "Rapid Accumulation of Variations in Exposed Residues" (RAVER) by analyzing the nucleotide sequences .…”

Section: Studying Venom Evolutionmentioning

confidence: 96%

“…These new capabilities have expanded our knowledge of the pharmacological profiles of venoms, helped produce better antivenoms through the field of antivenomics (Calvete et al, 2009;Calvete, 2010;Gutierrez et al, 2009;Harrison et al, 2007;Pla et al, 2012), aided in the identification of toxins that could be used as tools for understanding normal physiological processes, and developed as diagnostic tools, research means, or prototypes of therapeutic drugs. Further, such systems approaches help us decipher the evolutionary history, expression profiles and regulation of expression of venom toxin genes (Doley et al, 2009). The cDNAs of individual toxins or chimeras representing several toxins have also been used in raising antibodies that can neutralize their toxic effects (Azofeifa-Cordero et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Venom gland transcriptomics for identifying, cataloging, and characterizing venom proteins in snakes

Brahma

McCleary

Kini

et al. 2015

Toxicon

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“…Despite their high sequence similarity, VVSPs differ widely in their functions. Accelerated evolution [12], exon switching [13] and point mutations [14] have been reported to be involved in the generation of novel VVSPs and adaption to different geographical locations and available prey. Due to their physiological and medical importance, understanding of VVSP sequences, structures, functions and phylogenetic relationships represent research priorities.…”

Section: Introductionmentioning

confidence: 99%

Sequence and phylogenetic analysis of viper venom serine proteases

Vaiyapuri¹,

Thiyagarajan²,

Hutchinson³

et al. 2012

Bioinformation

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Abstract:Snakebites are a major neglected tropical disease responsible for as many as 95000 deaths every year worldwide. Viper venom serine proteases disrupt haemostasis of prey and victims by affecting various stages of the blood coagulation system. A better understanding of their sequence, structure, function and phylogenetic relationships will improve the knowledge on the pathological conditions and aid in the development of novel therapeutics for treating snakebites. A large dataset for all available viper venom serine proteases was developed and analysed to study various features of these enzymes. Despite the large number of venom serine protease sequences available, only a small proportion of these have been functionally characterised. Although, they share some of the common features such as a C-terminal extension, GWG motif and disulphide linkages, they vary widely between each other in features such as isoelectric points, potential N-glycosylation sites and functional characteristics. Some of the serine proteases contain substitutions for one or more of the critical residues in catalytic triad or primary specificity pockets. Phylogenetic analysis clustered all the sequences in three major groups. The sequences with substitutions in catalytic triad or specificity pocket clustered together in separate groups. Our study provides the most complete information on viper venom serine proteases to date and improves the current knowledge on the sequence, structure, function and phylogenetic relationships of these enzymes. This collective analysis of venom serine proteases will help in understanding the complexity of envenomation and potential therapeutic avenues. Background:Snakebite is a major neglected public health issue particularly among agricultural communities living in rural regions throughout the world [1, 2]. An estimated 2.5 million people are bitten by snakes each year and these are estimated to result in up to as high as 95000 deaths worldwide . Snake venom serine proteases are major components and have been identified mainly in the venoms of snakes belonging to the viperidae family with a few occurring in members of the elapidae, colubridae and hydrophidae families [8]. Many snake venom serine proteases exert their effects through the ability to disrupt the normal haemostasis of envenomed prey and victims [9]. Indeed, viper venom serine proteases (VVSPs) affect various stages of the blood coagulation system, activate platelets and directly act upon fibrinogen. These include pro-coagulant

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Role of accelerated segment switch in exons to alter targeting (ASSET) in the molecular evolution of snake venom proteins

Cited by 56 publications

References 84 publications

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

Venom gland transcriptomics for identifying, cataloging, and characterizing venom proteins in snakes

Sequence and phylogenetic analysis of viper venom serine proteases

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