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Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.

Yu H, Lu Y, Qiao X, Wei L, Fu T, Cai S, Wang C, Liu X, Zhong S, Wang Y - Sci Rep (2015)

Bottom Line: In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways.Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway.Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.

ABSTRACT
Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia. Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

No MeSH data available.


Related in: MedlinePlus

The cDNA sequence encoding Cl-CATH2 and Cl-CATH3 (Columba livia) as well as the deduced precursor amino acid sequence.The predicted signal peptides of Cl-CATHs are shown in italic and deduced mature peptides of Cl-CATHs are boxed. (*) indicates the stop codon.
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f1: The cDNA sequence encoding Cl-CATH2 and Cl-CATH3 (Columba livia) as well as the deduced precursor amino acid sequence.The predicted signal peptides of Cl-CATHs are shown in italic and deduced mature peptides of Cl-CATHs are boxed. (*) indicates the stop codon.

Mentions: From the cDNA library constructed, two clones encoding two novel cathelicidins were isolated and sequenced. The deduced 156-aa and 149-aa precursors both contain a 17-aa N-terminal signal domain predicted by signalp 3.0 (Fig. 1). Sequence alignments showed that avian cathelicidins all share same gene structure: a signal peptide followed by a conserved cathelin domain with four invariantly spaced cysteines and a cationic C-terminal mature antimicrobial peptide (see Supplementary Fig. S1 online). Two mature peptides were predicted, Cl-CATH2 (LIQRGRFGRFLGRIRRFRPRINFDIRARGSIRLG, 34aa) (GenBank Access number: KP645199) and Cl-CATH3 (RVKRFWPLVPVAINTVAAGINLYKAIKRK, 29aa) (GenBank Access number: KP645200). The theoretical pI/Mw predicted using Protparam tool (http://au.expasy.org/tools/protparam.html) for Cl-CATH2 and 3 are 12.65/4127.92 and 11.75/3323.08, respectively.


Novel Cathelicidins from Pigeon Highlights Evolutionary Convergence in Avain Cathelicidins and Functions in Modulation of Innate Immunity.

Yu H, Lu Y, Qiao X, Wei L, Fu T, Cai S, Wang C, Liu X, Zhong S, Wang Y - Sci Rep (2015)

The cDNA sequence encoding Cl-CATH2 and Cl-CATH3 (Columba livia) as well as the deduced precursor amino acid sequence.The predicted signal peptides of Cl-CATHs are shown in italic and deduced mature peptides of Cl-CATHs are boxed. (*) indicates the stop codon.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508531&req=5

f1: The cDNA sequence encoding Cl-CATH2 and Cl-CATH3 (Columba livia) as well as the deduced precursor amino acid sequence.The predicted signal peptides of Cl-CATHs are shown in italic and deduced mature peptides of Cl-CATHs are boxed. (*) indicates the stop codon.
Mentions: From the cDNA library constructed, two clones encoding two novel cathelicidins were isolated and sequenced. The deduced 156-aa and 149-aa precursors both contain a 17-aa N-terminal signal domain predicted by signalp 3.0 (Fig. 1). Sequence alignments showed that avian cathelicidins all share same gene structure: a signal peptide followed by a conserved cathelin domain with four invariantly spaced cysteines and a cationic C-terminal mature antimicrobial peptide (see Supplementary Fig. S1 online). Two mature peptides were predicted, Cl-CATH2 (LIQRGRFGRFLGRIRRFRPRINFDIRARGSIRLG, 34aa) (GenBank Access number: KP645199) and Cl-CATH3 (RVKRFWPLVPVAINTVAAGINLYKAIKRK, 29aa) (GenBank Access number: KP645200). The theoretical pI/Mw predicted using Protparam tool (http://au.expasy.org/tools/protparam.html) for Cl-CATH2 and 3 are 12.65/4127.92 and 11.75/3323.08, respectively.

Bottom Line: In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways.Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway.Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

View Article: PubMed Central - PubMed

Affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.

ABSTRACT
Cathelicidins are short cationic host defense peptides and play a central role in host innate immune system. Here we identified two novel cathelicidins, Cl-CATH2 and 3, from Columba livia. Evolutionary analysis of avian cathelicidins via phylogenetic tree and Ka/Ks calculations supported the positive selection that prompted evolution of CATH2 to CATH1 and 3, which originate from common ancestor and could belong to one superfamily. Cl-CATH2 and 3 both adopt amphipathic α-helical comformations identified by circular dichroism and the 3D structures built by Rosetta. Cl-CATH2 of CATH2 family with the most expression abundance in bird, exhibited relatively weak antimicrobial activity, but acted instead on the innate immune response without showing undesirable toxicities. In macrophages primed by LPS, Cl-CATH2 significantly down-regulated the gene and protein expressions of inducible nitric oxide synthase and pro-inflammatory cytokines while enhancing the anti-inflammatory cytokine, acting through MAPK and NF-κB signaling pathways. Molecular docking shows for the first time that cathelicidin binds to the opening region of LPS-binding pocket on myeloid differentiation factor 2 (MD-2) of toll-like receptor (TLR)4-MD-2 complex, which in turn inhibits the TLR4 pathway. Our results, therefore, provide new insight into the mechanism underlying the blockade of TLR4 signaling by cathelicidins.

No MeSH data available.


Related in: MedlinePlus