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Three-finger protein

March 11, 2023

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]

Three-finger protein
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?
CATH1qkd
SCOP21qkd / SCOPe / SUPFAM

Three-finger toxins

Main article: Three-finger toxin

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.[7]

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]

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. ^ a b 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. ^ a b c d e f g h 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. ^ a b c 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. ^ a b 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. ^ a b c 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. ^ a b c 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. ^ a b 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. ^ a b 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.

External links

  • SCOP: SSF57302
  • CATH: 2.10.60.10

March 11, 2023
three, finger, protein, three, finger, protein, domains, tfpd, protein, superfamily, consisting, small, roughly, amino, acid, residue, protein, domains, with, common, tertiary, structure, three, beta, strand, loops, extended, from, hydrophobic, core, stabilize. 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 Three finger proteinErabutoxin 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 IdentifiersSymbol CATH1qkdSCOP21qkd SCOPe SUPFAM Contents 1 Three finger toxins 2 Ly6 uPAR family 3 Gene structure 4 Evolution and taxonomic distribution 5 References 6 External linksThree finger toxins EditMain article Three finger toxin 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 Edit The human CD59 protein which regulates the complement system 7 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 EditSnake 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 EditProteins 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 References Edit 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 a b 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 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 a b c d e f g h 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 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 Sanz L Pla D Perez A Rodriguez 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 PLA Dichotomy across Micrurus Venoms Toxins 8 6 178 doi 10 3390 toxins8060178 PMC 4926144 PMID 27338473 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 a b c 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 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 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 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 a b 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 a b c 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 a b c 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 a b Fry BG Casewell NR Wuster 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 a b 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 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 External links EditSCOP SSF57302 CATH 2 10 60 10 Retrieved from https en wikipedia org w index php title Three finger protein amp oldid 1077023754, wikipedia, wiki, book, books, library,

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