biostudies-literatureTakjoo RMerchant FoundationNational Cancer InstituteNCI NIH HHSNational Institutes of HealthDBT/Wellcome Trust India AllianceWellcome TrustNIH HHSAustralian Research CouncilJames Cook University415-426https://www.ebi.ac.uk/biostudies/studies/S-EPMC11891777biostudies-literatureUnknown15(3)Sea stars are an abundant group of marine invertebrates that display remarkably robust regenerative capabilities throughout all life stages. Numerous proteins and peptides have been identified in a proteome study on the coelomic fluid (biofluid) of the common sea star Asterias rubens, which appear to be involved with the wound-healing response in the organism. However, the three-dimensional structure and function of several of these injury-responsive peptides, including the peptide KASH2, are yet to be investigated. Here, we show that the KASH2 peptide adopts a disulfide-directed β-hairpin fold (DDH). The DDH motif appears to be evolutionarily related to the inhibitor cystine knot motif, which is one of the most widespread disulfide-rich peptide folds. The DDH motif was originally thought FEBS open bioStructural analysis of an Asterias rubens peptide indicates the presence of a disulfide-directed β-hairpin fold.PMC11891777FF110100226R01CA164719LE160100218IA/I/19/2/504647R01 CA164719Takjoo RSchmidt CASmout MJWilson DTDaly NLLiddell MJShaikh NYLe Quilliec JZhao GSunagar KLoukas AfalseStructural analysis of an Asterias rubens peptide indicates the presence of a disulfide-directed β-hairpin fold.Sea stars are an abundant group of marine invertebrates that display remarkably robust regenerative capabilities throughout all life stages. Numerous proteins and peptides have been identified in a proteome study on the coelomic fluid (biofluid) of the common sea star Asterias rubens, which appear to be involved with the wound-healing response in the organism. However, the three-dimensional structure and function of several of these injury-responsive peptides, including the peptide KASH2, are yet to be investigated. Here, we show that the KASH2 peptide adopts a disulfide-directed β-hairpin fold (DDH). The DDH motif appears to be evolutionarily related to the inhibitor cystine knot motif, which is one of the most widespread disulfide-rich peptide folds. The DDH motif was originally thought 2025-01-01T00:00:00Z2025 Mar2026-06-01T20:12:20.564Z2025-04-07T07:49:15.483ZS-EPMC118917773956126510.1002/2211-5463.13931