Tachyplesin: Difference between revisions

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Janak Raj Joshi, Shulamit Idzikowski, Michal Harel, Alexander Berchansky, Joel L. Sussman, Angel Herraez, Jaime Prilusky

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-<StructureSection load='1MA2' size='340' side='right' caption='[[1ma2]]' scene='67/671725/First_scene/2'>
+<StructureSection load='' size='340' side='right' caption='Tacyplesin I (PDB code [[1ma2]])' scene='67/671725/First_scene/2'>
 == Introduction ==
-Tachyplesin I (TP-I) is an [http://en.wikipedia.org/wiki/Antimicrobial_peptides antimicrobial polypeptide] originally detected in the leukocytes of Japanese [http://en.wikipedia.org/wiki/Horseshoe_crab Horse Shoe Crab]. It has been reported to inhibit the growth  of [http://en.wikipedia.org/wiki/Bacteria bacteria], [http://en.wikipedia.org/wiki/Fungus fungui] and [http://en.wikipedia.org/wiki/Virus viruses].
+'''Tachyplesin I, II and III''' are [http://en.wikipedia.org/wiki/Antimicrobial_peptides antimicrobial polypeptide] originally detected in the leukocytes of Japanese [http://en.wikipedia.org/wiki/Horseshoe_crab Horse Shoe Crab]. It has been reported to inhibit the growth  of [http://en.wikipedia.org/wiki/Bacteria bacteria], [http://en.wikipedia.org/wiki/Fungus fungui] and [http://en.wikipedia.org/wiki/Virus viruses].
 The antimicrobial activity of the polypeptide is contributed by electrostatic interaction between the negatively charged membrane of bacteria and fungi to positively charged part of <scene name='67/671725/Cationic_peptide_tpi/3'> TP-I </scene> <ref name=Laederach>PMID:12369825</ref> (see the {{Template:ColorKey_Hydrophobic}} and {{Template:ColorKey_Charge_Cationic}} amino acids).
 Specifically, TP-I shows high affinity for negatively charged [http://en.wikipedia.org/wiki/Lipopolysaccharide lipopolysaccharides (LPS)] of [http://en.wikipedia.org/wiki/Gram-negative_bacteria gram-negative bacteria], thus neutralizing its effects.
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 The sequence adapts an antiparallel β-sheet (hairpin) conformation in solution, with a <scene name='67/671725/Beta_turn_tp-1/2'>β-turn</scene> for the centrally located residues <scene name='67/671725/Tyrargglyile/3'>Tyr-Arg-Gly-Ile</scene>, stabilized by two cross-strand <scene name='67/671725/Disulfide_bonds/4'> disulfide bonds </scene>  between Cys³-Cys¹⁶ and Cys⁷-Cys¹²<ref name=Saravanan>PMID:22464970</ref><ref name=Nakamura>Nakamura, Takanori, et al. "Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (''Tachypleus tridentatus''). Isolation and chemical structure." Journal of Biological Chemistry 263.32 (1988): 16709-16713</ref>, and [http://en.wikipedia.org/wiki/Protein_primary_structure C-terminus amidation].  In addition there are H-bonds and aromatic rings stacking interactions which helps stabilize the hairpin loop structure of the peptide.
-[http://en.wikipedia.org/wiki/Nuclear_magnetic_resonance NMR] studies have shown that TP-I undergoes a conformational change in <scene name='67/671725/Tp_i_in_the_presence_of_lps/1'>presence of LPS, </scene><scene name='67/671725/Conformation_change/8'>making it more rigid and twisted than in the presence of water</scene><ref name=Kushibiki>PMID:24389234</ref>. Moreover docking model suggests the stabilized structure of TP-I in presence of LPS, which is gained by binding between N and C termini of TP-I to LPS. The conformational change of TP-I seems to be crucial for its antimicrobial activity, since rearrangement of TP-I structure makes it more amphiphilic to negatively charged membrane of bacteria and fungus<ref name=Laederach>PMID:12369825</ref>.
+[http://en.wikipedia.org/wiki/Nuclear_magnetic_resonance NMR] studies have shown that TP-I undergoes a conformational change from <scene name='67/671725/First_scene/5'>water  surrounding</scene>  to <scene name='67/671725/Tp_i_in_the_presence_of_lps/4'>presence of LPS</scene>, making it <scene name='67/671725/Conformation_change/16'>more rigid and twisted</scene> than in the presence of water<ref name=Kushibiki>PMID:24389234</ref>. Moreover a docking model suggests the stability of the structure of TP-I is increased in the presence of LPS by the binding of the N and C termini of TP-I to LPS. The conformational change of TP-I seems to be crucial for its antimicrobial activity, since rearrangement of TP-I structure makes it more amphiphilic to negatively charged membrane of bacteria and fungus<ref name=Laederach>PMID:12369825</ref>.
 == Derivatives or Analogue ==
-Among all the existing interactions, cysteine bridge being considered as the principal contributor of the structure, three linear derivatives of TP-I (<scene name='67/671725/1ma4/3'>TPY4</scene>, TPF4 and TPA4) were created, in which the bridging cysteine residues are uniformly replaced with tyrosine, phenylalanine, and alanine, respectively<ref name=Laederach>PMID:12369825</ref><ref name=Kushibiki>PMID:24389234</ref>. The linear derivatives of TP-I are mentioned below:
+Among all the existing interactions, the cysteine bridges were considered as the principal contributors of the hairpin loop structure. To test this, three linear derivatives of TP-I (<scene name='67/671725/1ma4/3'>TPY4</scene>, TPF4 and TPA4) were created, in which the bridging cysteine residues were systematically replaced with tyrosine, phenylalanine, and alanine, respectively<ref name=Laederach>PMID:12369825</ref><ref name=Kushibiki>PMID:24389234</ref>. The linear derivatives of TP-I are mentioned below:
-[[Image:Seq TPI.jpg|750px]]
+[[Image:Seq TPI.jpg|500px]]
-Of those 3 linear derivatives of TP-I, NMR structural investigation had shown TPA4 to be unstructured in solution. Also, TPA4 was inactive in terms of antimicrobial activity. In contrast, TPY4 and TPF4 adapts hairpin loop and also had antimicrobial properties, typical to TP-I. Therefore, the hairpin properties of the peptide seems to be important for recognition of lipopolysaccharides and its biological activities.
+Of these 3 linear derivatives of TP-I, NMR structural investigations had shown that TPA4 was unstructured in solution. Also, TPA4 was inactive in terms of antimicrobial activity. In contrast, TPY4 and TPF4 adapt hairpin loop structure and also retain their antimicrobial properties, typical to TP-I. Therefore, the hairpin properties of the peptide seems to be important for recognition of LPS and its biological activities.
-Besides replacement of cysteines, deletions was also performed in TP-I which yielded <scene name='67/671725/Cdt/1'>Cysteine Deleted Tachyplesin</scene> (CDT). Thus, CTD  with sequence NH₂-Lys-Trp-Phe-Arg-Val-Tyr-Arg-Gly-Ile-Tyr-Arg-Arg-Arg-CONH₂ did not have disulphide linkage, but was found to have broad spectrum of bactericidal activity. Specifically, CDT has been demonstrated to markedly inhibit the growth of [http://en.wikipedia.org/wiki/Escherichia_coli <i>Escherichia coli</i>] and [http://en.wikipedia.org/wiki/Listeria_monocytogenes <i>Listeria monocytogenes</i>] akin to TP-I, even with lower minimum inhibitory concentration (MIC) values.
+Besides replacement of cysteines, deletions were also performed in TP-I which yielded the surprising result of a hairpin loop that was seen, by NMR structure in LPS, in the <scene name='67/671725/Cdt/1'>Cysteine Deleted Tachyplesin</scene> (CDT). Thus, CTD  with sequence NH₂-Lys-Trp-Phe-Arg-Val-Tyr-Arg-Gly-Ile-Tyr-Arg-Arg-Arg-CONH₂ did not have disulphide linkage, but was found to have broad spectrum of bactericidal activity. Specifically, CDT has been demonstrated to markedly inhibit the growth of [http://en.wikipedia.org/wiki/Escherichia_coli <i>Escherichia coli</i>] and [http://en.wikipedia.org/wiki/Listeria_monocytogenes <i>Listeria monocytogenes</i>] akin to TP-I, even with lower minimum inhibitory concentration (MIC) values.
 <b><u> CDT Structure </u></b>
-CDT, like TP-I, has a β-turn in the <scene name='67/671725/Cdtturn/2'>same preserved residues</scene> in its LPS-bound structure.
+CDT, like TP-I, has a β-turn with the <scene name='67/671725/Cdtturn/2'>same preserved residues</scene> in its LPS-bound structure.
 The β-hairpin topology of CDT is sustained by the <scene name='67/671725/Cdthaipin/2'>unique packing interactions</scene> between the aromatic ring of Trp2 and the side-chain of nonpolar amino acid of Val5 and the cationic side-chain of residue Arg11.
 Also, there exists close proximity between residues <scene name='67/671725/Cdtnoe/1'>Trp2 and Ile9</scene> which is supported by [http://en.wikipedia.org/wiki/Nuclear_Overhauser_effect nuclear overhauser effects (NOEs)] involving [http://en.wikipedia.org/wiki/Indole indole] ring protons of Trp2 with side-chain proton of Ile9. These packing interactions have rendered an approximate anti-parallel orientation of the hairpin structure of CDT in presence of LPS.
-The β-hairpin like structure of CDT displays an extended <font color='darkblue'>positively charged</font> surface patch of <scene name='67/671725/Cdtr4r7r12r13/1'>residues Arg 4, 7, 12 and 13</scene>. These positively charged basic residues interacts with the anionic phosphate groups of LPS, that leads to a plausible disruption or fluidization of LPS structures. This facilitates traversal of the peptide through the LPS-outer membrane<ref name=Saravanan>PMID:22464970</ref>.
+The β-hairpin structure displays an extended <font color='darkblue'>positively charged</font> surface patch of residues <scene name='67/671725/Cdtr4r7r12r13/3'>Arg 4, 7, 12 and 13</scene>. These positively charged basic residues interacts with the anionic phosphate groups of LPS, that leads to a plausible disruption or fluidization of LPS structures. This facilitates traversal of the peptide through the LPS-outer membrane<ref name=Saravanan>PMID:22464970</ref>.
 == Mode of action ==
@@ Line 48: / Line 39: @@
 == Importance and relevance ==
-Evidences suggest that TP-I has ability to permeabilize the cell membranes of pathogens.<ref name=Laederach>PMID:12369825</ref>. Also, LPS and DNA being the potential biological targets of the peptide, its antimicrobial activity might be exploited. Eyeing the potential of TP-I, it has been insetred successfully in genome of ''Ornithogalum dubium'' and ''Ornithogalum thyrsoides''. These ornamentals plants were originally sensitive to soft rot erwinias (SREs) and insertion of TP-I in the plants has successfully protected them without affecting their normal physiology <ref name=Lipsky>PMID:25438795</ref>.
+<b><u> Plants and Agriculture </u></b>
-[http://en.wikipedia.org/wiki/Escherichia_coli <i>Escherichia coli</i>] and [http://en.wikipedia.org/wiki/Staphylococcus_aureus <i>Listeria monocytogenes</i>] are Gram-negative and Gram-positive bacteria, respectively. They are the most common intestinal tract pathogenic bacteria in animals and humans.
-Studying the effect of TP-I on <i>E. coli</i> and <i>S. aureus</i> will be valuable in guiding clinical practice.
-The potential mechanism of <i>E. coli</i> membrane disruption by TP-I is the induction of macromolecule leakage into the cytoplasm and the release of potassium ions, leading to an increase in inner permeability, the formation of a toroidal pore, the neutralization of LPS, and the disruption of the permeability barrier of the outer membrane. TP-I killed <i>E. coli</i> mainly through cell membrane damage and intracellular esterase inactivation dependent on concentration.
+Evidences suggest that TP-I has ability to permeabilize the cell membranes of pathogens.<ref name=Laederach>PMID:12369825</ref>. Also, LPS and DNA being the potential biological targets of the peptide, its antimicrobial activity might be exploited. Eyeing the potential of TP-I, it has been insetred successfully in genome of ''Ornithogalum dubium'' and ''Ornithogalum thyrsoides''. These ornamentals plants were originally sensitive to soft rot erwinias (SREs) and insertion of TP-I in the plants has successfully protected them without affecting their normal physiology <ref name=Lipsky>PMID:25438795</ref><ref name=Lipsky and Joshi>PMID:27639550</ref>.
-In food production, requirements must be met for producing high quality food with minimal microbial contamination, and the determination of microbial viability based on different physiological and metabolic parameters is critical for acceptable sterilization. Therefore, the presence of injured, metabolically active bacteria is a very important aspect to consider in food production and for clinical applications. Sub lethally injured cells might be repaired under suitable conditions. If TP-I is applied as a clinical treatment at a lower concentration than the [http://en.wikipedia.org/wiki/Minimum_inhibitory_concentration MIC] over a long period of time, drug resistance could develop.<ref name=Hong>Hong, Jun, et al. "Mechanism of tachyplesin I injury to bacterial membrane and intracellular enzymes, determined by laser confocal scanning microscopy and flow cytometry." Microbiological research (2014).‏</ref>
+<b><u> Clinical Importance </u></b>
+Unlike mammalian cell membrane, bacterial cell membrane are negatively charged. [http://en.wikipedia.org/wiki/Escherichia_coli <i>Escherichia coli</i>] and [http://en.wikipedia.org/wiki/Staphylococcus_aureus <i>Listeria monocytogenes</i>] being most common pathogenic bacteria in animals and humans, studying the effect of TP-I on <i>E. coli</i> and <i>S. aureus</i> will be valuable in guiding clinical practice. The study in <i>E. coli</i> has shown membrane disruption upon treatment with TP-I. Also macromolecule leakage into the cytoplasm and the release of potassium ions was observed that ultimately killed <i>E. coli</i><ref name=Hong>Hong, Jun, et al. "Mechanism of tachyplesin I injury to bacterial membrane and intracellular enzymes, determined by laser confocal scanning microscopy and flow cytometry." Microbiological research (2014)‏</ref>.
 == Possible Function as anti-tumor peptide ==
 The cationic nature of Tachyplesin allows it to interact with anionic phospholipids present in the bacterial membrane and thereby disrupting membrane function. Besides this, the structural nature of Tachyplesin also highlights its antitumor properties. Since it can interact with the membrance of prokaryotic cell, it is likely that TP-I can also interact with the mitochondrial membrane of eukaryotic cells. Mitochondria are widely believed to have evolved from prokaryotic cells, that have established a symbiotic relationship with the primitive eukaryotic cell which signifies the structural similarity of mitochondrial and prokaryotic membranes.
-It was found that the synthetic Tachyplesin conjugated to the integrin homing domain (RGD-Tachyplesin) can inhibit the [http://en.wikipedia.org/wiki/Cell_growth proliferation] of TSU tumor cells [http://en.wikipedia.org/wiki/Prostate_cancer prostate cancer]  and B16 [http://en.wikipedia.org/wiki/Melanoma melanoma] cells as well as [http://en.wikipedia.org/wiki/Endothelium endothelial cells] in a dose-dependent manner <i>in vitro</i> and reduce tumor growth <i>in vivo</i> by inducing [http://en.wikipedia.org/wiki/Apoptosis apoptosis].<ref name=Chen>PMID:11289111‏</ref>. Besides this RGD-Tachyplesin can activate caspases and induce Fas ligand, which are the markers for programmed cell death (PCD). Collectively, suppression of tumor associated cell and induction of programmed cell death will eventually act as therapy for cancer and tumor cells.
+It was found that the synthetic Tachyplesin conjugated to the integrin homing domain (RGD-Tachyplesin) can inhibit the [http://en.wikipedia.org/wiki/Cell_growth proliferation] of TSU tumor cells [http://en.wikipedia.org/wiki/Prostate_cancer prostate cancer]  and B16 [http://en.wikipedia.org/wiki/Melanoma melanoma] cells as well as [http://en.wikipedia.org/wiki/Endothelium endothelial cells] in a dose-dependent manner <i>in vitro</i> and reduce tumor growth <i>in vivo</i> by inducing [http://en.wikipedia.org/wiki/Apoptosis apoptosis].<ref name=Chen>PMID:11289111‏</ref>. Besides this RGD-Tachyplesin can activate caspases and induce Fas ligand, which are the markers for programmed cell death (PCD)<ref name=Ellrby>Ellerby, H. Michael, et al. "Anti-cancer activity of targeted pro-apoptotic peptides." Nature Medicine(1999)‏</ref>.
+Collectively, suppression of tumor associated cell and induction of programmed cell death will eventually act as therapy for cancer and tumor cells.
+==3D structure of tachyplesin==
+Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
+{{#tree:id=OrganizedByTopic|openlevels=0|
+*Tachyplesin I
+**[[1ma2]], [[1ma5]], [[1wo0]], [[1wo1]], [[2mdb]], [[2rtv]], [[6pin]] – TtTacI peptide residues 24-40  – Tachypleus tridentatus -  - NMR<br />
+**[[1ma4]], [[1ma6]] – TtTacI peptide residues 24-40 (mutant) - NMR<br />
+**[[2lm8]] – TacI peptide residues 1-13 (mutant) - NMR<br />
-==See Also==
+*Tachyplesin II
-*[[Tachyplesin I 3D structures]]
+**[[6pio]] – TtTacII peptide residues 24-40  - NMR<br />
+**[[6pi2]] – TacII peptide residues 24-40  - Limulus polyphemus - NMR<br />
+*Tachyplesin III
+**[[6pip]], [[6pi3]] – TacIII + peptide residues 24-40  - Tachypleus gigas - NMR<br />
+}}
 == Quiz ==
@@ Line 83: / Line 87: @@
 {What is the secondery structure of TP-I?}
-+ Two antiparallel β-sheet
++ Two antiparallel β-strands
 - Two antiparallel α-Helixes
-- Two parallel β-sheet
+- Two parallel β-strands
 - Two parallel α-Helixes
@@ Line 91: / Line 95: @@
 - TPF4
 - TPY4
-- TPA4
++ TPA4
 - CDT
@@ Line 107: / Line 111: @@
 </Quiz>
-</StructureSection>
 == References ==
 <references/>
+</StructureSection>
+[[Category:Topic Page]]
+[[Category:Pages with quizzes]]