Cargando…

In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins

As generalist parasitoid wasps, Leptopilina heterotoma are highly successful on many species of fruit flies of the genus Drosophila. The parasitoids produce specialized multi-strategy extracellular vesicle (EV)-like structures in their venom. Proteomic analysis identified several immunity-associated...

Descripción completa

Detalles Bibliográficos
Autores principales: Arguelles, Joseph, Lee, Jenny, Cardenas, Lady V., Govind, Shubha, Singh, Shaneen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865768/
https://www.ncbi.nlm.nih.gov/pubmed/36678491
http://dx.doi.org/10.3390/pathogens12010143
_version_ 1784875921043357696
author Arguelles, Joseph
Lee, Jenny
Cardenas, Lady V.
Govind, Shubha
Singh, Shaneen
author_facet Arguelles, Joseph
Lee, Jenny
Cardenas, Lady V.
Govind, Shubha
Singh, Shaneen
author_sort Arguelles, Joseph
collection PubMed
description As generalist parasitoid wasps, Leptopilina heterotoma are highly successful on many species of fruit flies of the genus Drosophila. The parasitoids produce specialized multi-strategy extracellular vesicle (EV)-like structures in their venom. Proteomic analysis identified several immunity-associated proteins, including the knottin peptide, LhKNOT, containing the structurally conserved inhibitor cysteine knot (ICK) fold, which is present in proteins from diverse taxa. Our structural and docking analysis of LhKNOT’s 36-residue core knottin fold revealed that in addition to the knottin motif itself, it also possesses a Cation–Polar–Cation (CPC) clip. The CPC clip motif is thought to facilitate antimicrobial activity in heparin-binding proteins. Surprisingly, a majority of ICKs tested also possess the CPC clip motif, including 75 bona fide plant and arthropod knottin proteins that share high sequence and/or structural similarity with LhKNOT. Like LhKNOT and these other 75 knottin proteins, even the Drosophila Drosomycin antifungal peptide, a canonical target gene of the fly’s Toll-NF-kappa B immune pathway, contains this CPC clip motif. Together, our results suggest a possible defensive function for the parasitoid LhKNOT. The prevalence of the CPC clip motif, intrinsic to the cysteine knot within the knottin proteins examined here, suggests that the resultant 3D topology is important for their biochemical functions. The CPC clip is likely a highly conserved structural motif found in many diverse proteins with reported heparin binding capacity, including amyloid proteins. Knottins are targets for therapeutic drug development, and insights into their structure–function relationships will advance novel drug design.
format Online
Article
Text
id pubmed-9865768
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-98657682023-01-22 In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins Arguelles, Joseph Lee, Jenny Cardenas, Lady V. Govind, Shubha Singh, Shaneen Pathogens Article As generalist parasitoid wasps, Leptopilina heterotoma are highly successful on many species of fruit flies of the genus Drosophila. The parasitoids produce specialized multi-strategy extracellular vesicle (EV)-like structures in their venom. Proteomic analysis identified several immunity-associated proteins, including the knottin peptide, LhKNOT, containing the structurally conserved inhibitor cysteine knot (ICK) fold, which is present in proteins from diverse taxa. Our structural and docking analysis of LhKNOT’s 36-residue core knottin fold revealed that in addition to the knottin motif itself, it also possesses a Cation–Polar–Cation (CPC) clip. The CPC clip motif is thought to facilitate antimicrobial activity in heparin-binding proteins. Surprisingly, a majority of ICKs tested also possess the CPC clip motif, including 75 bona fide plant and arthropod knottin proteins that share high sequence and/or structural similarity with LhKNOT. Like LhKNOT and these other 75 knottin proteins, even the Drosophila Drosomycin antifungal peptide, a canonical target gene of the fly’s Toll-NF-kappa B immune pathway, contains this CPC clip motif. Together, our results suggest a possible defensive function for the parasitoid LhKNOT. The prevalence of the CPC clip motif, intrinsic to the cysteine knot within the knottin proteins examined here, suggests that the resultant 3D topology is important for their biochemical functions. The CPC clip is likely a highly conserved structural motif found in many diverse proteins with reported heparin binding capacity, including amyloid proteins. Knottins are targets for therapeutic drug development, and insights into their structure–function relationships will advance novel drug design. MDPI 2023-01-14 /pmc/articles/PMC9865768/ /pubmed/36678491 http://dx.doi.org/10.3390/pathogens12010143 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Arguelles, Joseph
Lee, Jenny
Cardenas, Lady V.
Govind, Shubha
Singh, Shaneen
In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins
title In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins
title_full In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins
title_fullStr In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins
title_full_unstemmed In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins
title_short In Silico Analysis of a Drosophila Parasitoid Venom Peptide Reveals Prevalence of the Cation–Polar–Cation Clip Motif in Knottin Proteins
title_sort in silico analysis of a drosophila parasitoid venom peptide reveals prevalence of the cation–polar–cation clip motif in knottin proteins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865768/
https://www.ncbi.nlm.nih.gov/pubmed/36678491
http://dx.doi.org/10.3390/pathogens12010143
work_keys_str_mv AT arguellesjoseph insilicoanalysisofadrosophilaparasitoidvenompeptiderevealsprevalenceofthecationpolarcationclipmotifinknottinproteins
AT leejenny insilicoanalysisofadrosophilaparasitoidvenompeptiderevealsprevalenceofthecationpolarcationclipmotifinknottinproteins
AT cardenasladyv insilicoanalysisofadrosophilaparasitoidvenompeptiderevealsprevalenceofthecationpolarcationclipmotifinknottinproteins
AT govindshubha insilicoanalysisofadrosophilaparasitoidvenompeptiderevealsprevalenceofthecationpolarcationclipmotifinknottinproteins
AT singhshaneen insilicoanalysisofadrosophilaparasitoidvenompeptiderevealsprevalenceofthecationpolarcationclipmotifinknottinproteins