Referenced in: none

Automatically associated channels: Slo1

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

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

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2016 Apr 26 , 113, E2460-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/27071086

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 Thr(26) 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. Thr(26) phosphorylation leads to charge neutralization of Arg(24), a residue crucial for MCa agonist activity. The functional effect of Thr(26) 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.