In cellulo phosphorylation induces pharmacological reprogramming of maurocalcin, a cell-penetrating venom peptide

Michel Ronjat, Wei Feng, Lucie Dardevet, Yao Dong, Sawsan Al Khoury, Franck C. Chatelain, Virginie Vialla, Samir Chahboun, Florian Lesage, Hervé Darbon, Isaac N Pessah, Michel De Waard

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4 Scopus citations

Abstract

The venom peptide maurocalcin (MCa) is atypical among toxins because of its ability to rapidly translocate into cells and potently activate the intracellular calcium channel type 1 ryanodine receptor (RyR1). Therefore, MCa is potentially subjected to posttranslational modifications within recipient cells. Here, we report that MCa Thr26 belongs to a consensus PKA phosphorylation site and can be phosphorylated by PKA both in vitro and after cell penetration in cellulo. Unexpectedly, phosphorylation converts MCa from positive to negative RyR1 allosteric modulator. Thr26 phosphorylation leads to charge neutralization of Arg24, a residue crucial for MCa agonist activity. The functional effect of Thr26 phosphorylation is partially mimicked by aspartyl mutation. This represents the first case, to our knowledge, of both ex situ posttranslational modification and pharmacological reprogramming of a small natural cystine-rich peptide by target cells. So far, phosphorylated MCa is the first specific negative allosteric modulator of RyR1, to our knowledge, and represents a lead compound for further development of phosphatase-resistant analogs.

Original languageEnglish (US)
Pages (from-to)E2460-E2468
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number17
DOIs
StatePublished - Apr 26 2016

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Keywords

  • Maurocalcin
  • Pharmacology
  • Phosphorylation
  • Ryanodine receptor
  • Toxin

ASJC Scopus subject areas

  • General

Cite this

Ronjat, M., Feng, W., Dardevet, L., Dong, Y., Al Khoury, S., Chatelain, F. C., Vialla, V., Chahboun, S., Lesage, F., Darbon, H., Pessah, I. N., & De Waard, M. (2016). In cellulo phosphorylation induces pharmacological reprogramming of maurocalcin, a cell-penetrating venom peptide. Proceedings of the National Academy of Sciences of the United States of America, 113(17), E2460-E2468. https://doi.org/10.1073/pnas.1517342113