Aplysia allatotropin-related peptide and its newly identified D-amino acid-containing epimer both activate a receptor and a neuronal target

James W. Checco, Guo Zhang, Wang Ding Yuan, Zi Wei Le, Jian Jing, Jonathan V Sweedler

Research output: Contribution to journalArticle

Abstract

L-to D-residue isomerization is a post-translational modification (PTM) present in neuropeptides, peptide hormones, and peptide toxins from several animals. In most cases, the D-residue is critical for the biological function of the resulting D-amino acid-containing peptide (DAACP). Here, we provide an example in native neuropeptides in which the DAACP and its all-Lamino acid epimer are both active at their newly identified receptor in vitro and at a neuronal target associated with feeding behavior. On the basis of sequence similarity to a known DAACP from cone snail venom, we hypothesized that allatotropin-related peptide (ATRP), a neuropeptide from the neuroscience model organism Aplysia californica, may form multiple diastereomers in the Aplysia central nervous system. We determined that ATRP exists as a D-amino acid-containing peptide (D2-ATRP) and identified a specificGprotein-coupled receptor as an ATRP receptor. Interestingly, unlike many previously reported DAACPs and their all-L-residue analogs, both L-ATRP and D2-ATRP were potent agonists of this receptor and active in electrophysiological experiments. Finally, D2-ATRP was much more stable than its all-L-residue counterpart in Aplysia plasma, suggesting that in the case of ATRP, the primary role of the L-to D-residue isomerization may be to protect this peptide from aminopeptidase activity in the extracellular space. Our results indicate that L-toD-residue isomerization can occur even in an all-L-residue peptide with aknownbiological activity and that insomecases, this PTMmayhelp modulate peptide signal lifetime in the extracellular space rather than activity at the cognate receptor.

Original languageEnglish (US)
Pages (from-to)16862-16873
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number43
DOIs
StatePublished - Jan 1 2018

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Aplysia
Amino Acids
Peptides
Neuropeptides
Isomerization
Extracellular Space
allatotropin
Mollusk Venoms
Aminopeptidases
Peptide Receptors
Peptide Hormones
Feeding Behavior
Post Translational Protein Processing
Neurosciences
Protein Sorting Signals
Neurology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Aplysia allatotropin-related peptide and its newly identified D-amino acid-containing epimer both activate a receptor and a neuronal target. / Checco, James W.; Zhang, Guo; Yuan, Wang Ding; Le, Zi Wei; Jing, Jian; Sweedler, Jonathan V.

In: Journal of Biological Chemistry, Vol. 293, No. 43, 01.01.2018, p. 16862-16873.

Research output: Contribution to journalArticle

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T1 - Aplysia allatotropin-related peptide and its newly identified D-amino acid-containing epimer both activate a receptor and a neuronal target

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AU - Zhang, Guo

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AU - Le, Zi Wei

AU - Jing, Jian

AU - Sweedler, Jonathan V

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