Identification of evolutionarily conserved residues required for the bioactivity of a pedal peptide/orcokinin-type neuropeptide

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2018-05, Vol.103, p.10-18
• Main Authors: Kim, Chan-Hee, Go, Hye-Jin, Oh, Hye Young, Elphick, Maurice R., Park, Nam Gyu
• Format: Article
• Language: English
• Subjects: Alanyl-substitued analog; Animals; Hydrophobic and Hydrophilic Interactions; Neuropeptides - chemistry; Neuropeptides - metabolism; Neuropeptides - pharmacology; Pedal peptide/orcokinin-type neuropeptide; SMP-like peptide; Starfish - metabolism; Starfish myorelaxant peptide; Structure-Activity Relationship; Truncated analog
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2018.03.007

Starfish myorelaxant peptide (SMP) belongs to a bilaterian family of pedal peptide/orcokinin (PP/OK)-type neuropeptides that have evolutionarily conserved structural features. Here we report the first analysis of the structure-activity relationships of SMP and identify key residues for SMP bioactivity, including hydrophobic residues located in the N- and C-terminal regions that are conserved in PP/OK-type peptides in other phyla as well as core residues that are only conserved in echinoderm PP/OK-type peptides. [Display omitted] •Hydrophobic residues (Phe1, Phe14, and Leu10) in SMP are important for bioactivity.•The hydrophobic residues are evolutionarily conserved in bilaterian PP/OK-type neuropeptides.•Core residues (Tyr7, Asp8, and Pro9) in SMP are important for bioactivity.•The core residues are key residues in deuterostomian PP/OK-type neuropeptides. Pedal peptides and orcokinins are structurally related neuropeptides that were first discovered in protostomian invertebrates – mollusks and arthropods, respectively. Recently, pedal peptide/ocokinin (PP/OK)-type neuropeptides were discovered in a deuterostomian phylum, the echinoderms, indicating that the evolutionary origin of this neuropeptide family can be traced back to the common ancestor of bilaterian animals. Sequences comparison of PP/OK-type neuropeptides reveals several conserved residues, including N- and C-terminally located hydrophobic residues that are important for the bioactivity of orcokinin. Here we report the first comprehensive analysis of the structure-activity relationships of a PP/OK-type neuropeptide – starfish myorelaxant peptide (SMP; FGKGGAYDPLSAGFTD) from the starfish Patiria pectinifera (Phylum Echinodermata). Comparison of the bioactivity of SMP with N-terminally and/or C-terminally truncated and alanine-substituted SMP analogs revealed a core peptide (GAYDPLSAGF; SMP(5-14)) that retains the muscle-relaxing activity of SMP, albeit with reduced potency and efficacy. Within this core peptide, alanine-substitution of several residues resulted in complete or partial loss of bioactivity, whilst loss or substitution of the N-terminal phenylalanine residue of SMP also caused a substantial reduction in bioactivity. Furthermore, analysis of the bioactivity of other SMP-like peptides derived from the same precursor as SMP revealed that none of these were more potent/effective than SMP as muscle relaxants. In conclusion, we have identified key residues required for the bioactivity of a