Three-finger protein

Last updated
Three-finger protein
1qkd 3ftx.png
Erabutoxin A, a neurotoxin that is a member of the three-finger toxin superfamily. The three "fingers" are labeled I, II, and III, and the four conserved disulfide bonds are shown in yellow. Rendered from PDB: 1QKD ​. [1]
Identifiers
Symbol?
CATH 1qkd
SCOP2 1qkd / SCOPe / SUPFAM

Three-finger proteins or three-finger protein domains (3FP or TFPD) are a protein superfamily consisting of small, roughly 60-80 amino acid residue protein domains with a common tertiary structure: three beta strand loops extended from a hydrophobic core stabilized by disulfide bonds. The family is named for the outstretched "fingers" of the three loops. Members of the family have no enzymatic activity, but are capable of forming protein-protein interactions with high specificity and affinity. The founding members of the family, also the best characterized by structure, are the three-finger toxins found in snake venom, which have a variety of pharmacological effects, most typically by disruption of cholinergic signaling. The family is also represented in non-toxic proteins, which have a wide taxonomic distribution; 3FP domains occur in the extracellular domains of some cell-surface receptors as well as in GPI-anchored and secreted globular proteins, usually involved in signaling. [2] [3] [4] [5]

Contents

Three-finger toxins

The founding members of the 3FP family are the three-finger toxins (3FTx) often found in snake venom. 3FTx proteins are widely distributed in venomous snake families, but are particularly enriched in the family Elapidae, in which the relative proportion of 3FTx to other venom toxins can reach 95%. [4] [6] Many 3FTx proteins are neurotoxins, though the mechanism of toxicity varies significantly even among proteins of relatively high sequence identity; common protein targets include those involved in cholinergic signaling, such as the nicotinic acetylcholine receptors, muscarinic acetylcholine receptors, and acetylcholinesterase. Another large subfamily of 3FTx proteins is the cardiotoxins (also known as cytotoxins or cytolysins); this group is directly cytotoxic most likely due to interactions with phospholipids and possibly other components of the cell membrane. [2]

Ly6/uPAR family

The human CD59 protein, which regulates the complement system. CD59 2j8b.png
The human CD59 protein, which regulates the complement system.

The Ly6/uPAR family broadly describes a gene family containing three-finger protein domains that are not toxic and not venom components; these are often known as LU domains and can be found in the extracellular domains of cell-surface receptors and in either GPI-anchored or secreted globular proteins. [4] [8] The family is named for two representative groups of members, the small globular protein lymphocyte antigen 6 (LY6) family and the urokinase plasminogen activator receptor (uPAR). [9] Other receptors with LU domains include members of the transforming growth factor beta receptor (TGF-beta) superfamily, such as the activin type 2 receptor; [10] and bone morphogenetic protein receptor, type IA. [11] Other LU domain proteins are small globular proteins such as CD59 antigen, LYNX1, SLURP1, and SLURP2. [4] [12]

Many LU domain containing proteins are involved in cholinergic signaling and bind acetylcholine receptors, notably linking their function to a common mechanism of 3FTx toxicity. [4] [8] [13] Members of the Ly6/uPAR family are believed to be the evolutionary ancestors of 3FTx toxins. [14] Other LU proteins, such as the CD59 antigen, have well-studied functions in regulation of the immune system. [13]

Gene structure

Snake three-finger toxins and the Ly6/uPAR family members share a common gene structure, typically consisting of two introns and three exons. The sequence of the first exon is generally well conserved compared to the other two. [4] The third exon contains the major differentiating features between the two groups, as this is where the C-terminal GPI-anchor peptide common among the Ly6/uPAR globular proteins is encoded. [4] [13]

Evolution and taxonomic distribution

Proteins of the general three-finger fold are widely distributed among metazoans. [4] A 2008 bioinformatics study identified about 45 examples of such proteins, containing up to three three-finger domains, represented in the human genome. [12] A more recent profile of the Ly6/uPAR gene family identified 35 human and at least 61 mouse family members in the organisms' respective genomes. [8]

The three-finger protein family is thought to have expanded through gene duplication in the snake lineage. [14] [15] 3FTx toxins are considered restricted to the Caenophidia, the taxon containing all venomous snakes; however at least one homolog has been identified in the Burmese python, a closely related subgroup. [16] Traditionally, 3FTx genes have been thought to have evolved by repeated events of duplication followed by neofunctionalization and recruitment to gene expression patterns restricted to venom glands. [14] [15] However, it has been argued that this process should be extremely rare and that subfunctionalization better explains the observed distribution. [17] More recently, non-toxic 3FP proteins have been found to be widely expressed in many different tissues in snakes, prompting the alternative hypothesis that proteins of restricted expression in saliva were selectively recruited for toxic functionality. [16]

Related Research Articles

<span class="mw-page-title-main">Venom</span> Toxin secreted by an animal

Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved venom apparatus, such as fangs or a stinger, in a process called envenomation. Venom is often distinguished from poison, which is a toxin that is passively delivered by being ingested, inhaled, or absorbed through the skin, and toxungen, which is actively transferred to the external surface of another animal via a physical delivery mechanism.

<span class="mw-page-title-main">Nicotinic acetylcholine receptor</span> Acetylcholine receptors named for their selective binding of nicotine

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.

<span class="mw-page-title-main">Snake venom</span> Highly modified saliva containing zootoxins

Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are also able to spit venom.

α-Bungarotoxin Chemical compound

α-Bungarotoxin is one of the bungarotoxins, components of the venom of the elapid Taiwanese banded krait snake. It is a type of α-neurotoxin, a neurotoxic protein that is known to bind competitively and in a relatively irreversible manner to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure, and death in the victim. It has also been shown to play an antagonistic role in the binding of the α7 nicotinic acetylcholine receptor in the brain, and as such has numerous applications in neuroscience research.

<span class="mw-page-title-main">Calciseptine</span> Neurotoxin

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

Taipoxin is a potent myo- and neurotoxin that was isolated from the venom of the coastal taipan Oxyuranus scutellatus or also known as the common taipan. Taipoxin like many other pre-synaptic neurotoxins are phospholipase A2 (PLA2) toxins, which inhibit/complete block the release of the motor transmitter acetylcholine and lead to death by paralysis of the respiratory muscles (asphyxia). It is the most lethal neurotoxin isolated from any snake venom to date.

Bungarotoxins are toxins found in the venom of snakes and kraits. Bites from these animals can result in severe symptoms including bleeding or hemorrhage, paralysis and tissue damage that can result in amputation. The paralytic effects of venom are particularly dangerous as they can impair breathing. These symptoms are the result of bungarotoxin presence in the venom. In actuality, venom contains several distinct bungarotoxins, each varying in which receptors they act on and how powerful they are.

<span class="mw-page-title-main">Cobratoxin</span> Chemical compound

α-Cobratoxin is a substance of the venom of certain Naja cobras. It is a nicotinic acetylcholine receptor (nAChR) antagonist which causes paralysis by preventing the binding of acetylcholine to the nAChR.

<span class="mw-page-title-main">Choline transporter</span> Protein-coding gene in the species Homo sapiens

The high-affinity choline transporter (ChT) also known as solute carrier family 5 member 7 is a protein in humans that is encoded by the SLC5A7 gene. It is a cell membrane transporter and carries choline into acetylcholine-synthesizing neurons.

<span class="mw-page-title-main">LU domain</span> Protein domain

The LU domain is an evolutionarily conserved protein domain of the three-finger protein superfamily. This domain is found in the extracellular domains of cell-surface receptors and in either GPI-anchored or secreted globular proteins, for example the Ly-6 family, CD59, and Sgp-2.

<span class="mw-page-title-main">Alpha-neurotoxin</span> Group of neurotoxic peptides found in the venom of snakes

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

<span class="mw-page-title-main">Mambalgins</span>

Mambalgins are peptides found in the venom of the black mamba, an elapid snake. Mambalgins are members of the three-finger toxin (3FTx) protein family and have the characteristic three-finger protein fold. First reported by French researchers in 2012, mambalgins are unusual members of the 3FTx family in that they have the in vivo effect of causing analgesia without apparent toxicity. Their mechanism of action is potent inhibition of acid-sensing ion channels.

<span class="mw-page-title-main">Evolution of snake venom</span> Origin and diversification of snake venom through geologic time

Venom in snakes and some lizards is a form of saliva that has been modified into venom over its evolutionary history. In snakes, venom has evolved to kill or subdue prey, as well as to perform other diet-related functions. While snakes occasionally use their venom in self defense, this is not believed to have had a strong effect on venom evolution. The evolution of venom is thought to be responsible for the enormous expansion of snakes across the globe.

<span class="mw-page-title-main">Three-finger toxin</span> Toxin protein

Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).

<span class="mw-page-title-main">Irditoxin</span>

Irditoxin is a three-finger toxin (3FTx) protein found in the venom of the brown tree snake and likely in other members of the genus Boiga. It is a heterodimer composed of two distinct protein chains, each of the three-finger protein fold, linked by an intermolecular disulfide bond. This structure is unusual for 3FTx proteins, which are most commonly monomeric.

Mipartoxin-I is a neurotoxin produced by Micrurus mipartitus, a venomous coral snake distributed in Central and South America. This toxin causes a neuromuscular blockade by blocking the nicotinic acetylcholine receptor. It is the most abundant component in the venom.

Long neurotoxin 1 (LNTX-1) is a neurotoxin that binds antagonistically to all types of muscular and neuronal nicotinic acetylcholine receptors. LNTX-1 is found in the venom of the king cobra.

Crotoxin (CTX) is the main toxic compound in the snake venom of the South American rattlesnake, Crotalus durissus terrificus. Crotoxin is a heterodimeric beta-neurotoxin, composed of an acidic, non-toxic and non-enzymatic subunit (CA), and a basic, weakly toxic, phospholipase A2 protein (CB). This neurotoxin causes paralysis by both pre- and postsynaptic blocking of acetylcholine signalling.

<span class="mw-page-title-main">LYPD6B</span> Protein-coding gene in the species Homo sapiens

LY6/PLAUR Domain Containing 6B, also known under the name Cancer/Testis Antigen 116 (CTA116) and LYPD7 is encoded by the LYPD6B gene. LYPD6B is a member of the lymphocyte antigen 6 (LY6) protein family. It is expressed in the testis, lungs, stomach, prostate and in the nervous system where it acts as a modulator of nicotinic acetylcholine receptor (nAChRs) activity.

Venomics is the large-scale study of proteins associated with venom. Venom is a toxic substance secreted by animals, which is typically injected either offensively or defensively into prey or aggressors, respectively.

References

  1. ↑ Nastopoulos V, Kanellopoulos PN, Tsernoglou D (September 1998). "Structure of dimeric and monomeric erabutoxin a refined at 1.5 A resolution" (PDF). Acta Crystallographica. Section D, Biological Crystallography. 54 (Pt 5): 964–74. doi:10.1107/S0907444998005125. PMID   9757111.
  2. 1 2 Kini RM, Doley R (November 2010). "Structure, function and evolution of three-finger toxins: mini proteins with multiple targets". Toxicon. 56 (6): 855–67. doi:10.1016/j.toxicon.2010.07.010. PMID   20670641.
  3. ↑ Hegde RP, Rajagopalan N, Doley R, Kini M (2010). "Snake venom three-finger toxins". In Mackessy SP (ed.). Handbook of venoms and toxins of reptiles. Boca Raton: CRC Press. pp. 287–302. ISBN   9781420008661.
  4. 1 2 3 4 5 6 7 8 Kessler P, Marchot P, Silva M, Servent D (August 2017). "The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions". Journal of Neurochemistry. 142 Suppl 2: 7–18. doi: 10.1111/jnc.13975 . PMID   28326549.
  5. ↑ Utkin Y, Sunagar K, Jackson TN, Reeks T, Fry BG (2015). "Chapter 8: Three-finger toxins". In Fry B (ed.). Venomous Reptiles and Their Toxins: Evolution, Pathophysiology and Biodiscovery. Oxford University Press. pp. 218–227. ISBN   9780199309405.
  6. ↑ Sanz L, Pla D, Pérez A, Rodríguez Y, Zavaleta A, Salas M, Lomonte B, Calvete JJ (June 2016). "Venomic Analysis of the Poorly Studied Desert Coral Snake, Micrurus tschudii tschudii, Supports the 3FTx/PLA₂ Dichotomy across Micrurus Venoms". Toxins. 8 (6): 178. doi: 10.3390/toxins8060178 . PMC   4926144 . PMID   27338473.
  7. ↑ Leath KJ, Johnson S, Roversi P, Hughes TR, Smith RA, Mackenzie L, Morgan BP, Lea SM (August 2007). "High-resolution structures of bacterially expressed soluble human CD59". Acta Crystallographica. Section F, Structural Biology and Crystallization Communications. 63 (Pt 8): 648–52. doi:10.1107/S1744309107033477. PMC   2335151 . PMID   17671359.
  8. 1 2 3 Loughner CL, Bruford EA, McAndrews MS, Delp EE, Swamynathan S, Swamynathan SK (April 2016). "Organization, evolution and functions of the human and mouse Ly6/uPAR family genes". Human Genomics. 10: 10. doi:10.1186/s40246-016-0074-2. PMC   4839075 . PMID   27098205.
  9. ↑ Ploug M, Ellis V (August 1994). "Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom alpha-neurotoxins". FEBS Letters. 349 (2): 163–8. doi: 10.1016/0014-5793(94)00674-1 . PMID   8050560. S2CID   86302713.
  10. ↑ Greenwald J, Fischer WH, Vale WW, Choe S (January 1999). "Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase". Nature Structural Biology. 6 (1): 18–22. doi:10.1038/4887. PMID   9886286. S2CID   26301441.
  11. ↑ Kirsch T, Sebald W, Dreyer MK (June 2000). "Crystal structure of the BMP-2-BRIA ectodomain complex". Nature Structural Biology. 7 (6): 492–6. doi:10.1038/75903. PMID   10881198. S2CID   19403233.
  12. 1 2 Galat A (November 2008). "The three-fingered protein domain of the human genome". Cellular and Molecular Life Sciences. 65 (21): 3481–93. doi:10.1007/s00018-008-8473-8. PMID   18821057. S2CID   19931506.
  13. 1 2 3 Tsetlin VI (February 2015). "Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: pharmacological tools and endogenous modulators". Trends in Pharmacological Sciences. 36 (2): 109–23. doi:10.1016/j.tips.2014.11.003. PMID   25528970.
  14. 1 2 3 Fry BG (March 2005). "From genome to "venome": molecular origin and evolution of the snake venom proteome inferred from phylogenetic analysis of toxin sequences and related body proteins". Genome Research. 15 (3): 403–20. doi:10.1101/gr.3228405. PMC   551567 . PMID   15741511.
  15. 1 2 Fry BG, Casewell NR, Wüster W, Vidal N, Young B, Jackson TN (September 2012). "The structural and functional diversification of the Toxicofera reptile venom system". Toxicon. Advancing in Basic and Translational Venomics. 60 (4): 434–48. doi:10.1016/j.toxicon.2012.02.013. PMID   22446061.
  16. 1 2 Reyes-Velasco J, Card DC, Andrew AL, Shaney KJ, Adams RH, Schield DR, Casewell NR, Mackessy SP, Castoe TA (January 2015). "Expression of venom gene homologs in diverse python tissues suggests a new model for the evolution of snake venom". Molecular Biology and Evolution. 32 (1): 173–83. doi: 10.1093/molbev/msu294 . PMID   25338510.
  17. ↑ Hargreaves AD, Swain MT, Hegarty MJ, Logan DW, Mulley JF (August 2014). "Restriction and recruitment-gene duplication and the origin and evolution of snake venom toxins". Genome Biology and Evolution. 6 (8): 2088–95. doi:10.1093/gbe/evu166. PMC   4231632 . PMID   25079342.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.