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In Cellulo Phosphorylation Induces Pharmacological Reprogramming of Maurocalcin, a Cell-Penetrating Venom Peptide

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In Cellulo Phosphorylation Induces Pharmacological Reprogramming of Maurocalcin, a Cell-Penetrating Venom Peptide In cellulo phosphorylation induces pharmacological reprogramming of maurocalcin, a cell-penetrating venom peptide Michel Ronjata,b,1,2, Wei Fengc,1, Lucie Dardeveta,b, Yao Dongc, Sawsan Al Khourya,b, Franck C. Chatelaind,e, Virginie Viallaa,b,f, Samir Chahbouna,b, Florian Lesaged,e, Hervé Darbong, Isaac N. Pessahc, and Michel De Waarda,b,f,2 aINSERM U836, LabEx Ion Channel, Science and Therapeutics, Grenoble Institute of Neuroscience, 38042 Grenoble, France; bUniversité Grenoble Alpes, 38042 Grenoble, France; cDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616; dCNRS UMR 7275, LabEx Ion Channel, Science and Therapeutics, Institut de Pharmacologie Moléculaire et Cellulaire, F-06560 Valbonne, France; eUniversité de Nice Sophia Antipolis, F-06560 Nice, France; fSmartox Biotechnologies, 38400 Saint-Martin d’Hères, France; and gArchitecture et Fonction des Macromolécules Biologiques-CNRS UMR 7257, Aix-Marseille Université, 13009 Marseille, France Edited by Andrew R. Marks, Columbia University College of Physicians & Surgeons, New York, NY, and approved February 25, 2016 (received for review August 31, 2015) The venom peptide maurocalcin (MCa) is atypical among toxins red lacks selectivity and cell permeability. On the agonist side, MCa because of its ability to rapidly translocate into cells and potently is a very informative pharmacologic tool to investigate RyR prop- activate the intracellular calcium channel type 1 ryanodine recep- erties because of its nanomolar potency and novel ability to sta- tor (RyR1). Therefore, MCa is potentially subjected to posttransla- bilize long-lived subconductances of the channel. Accordingly, tional modifications within recipient cells. Here, we report that MCa increases specific binding of [3H]-ryanodine to RyR1 with an MCa Thr26 belongs to a consensus PKA phosphorylation site and apparent affinity in the range of 10 to 50 nM (9). This effect results can be phosphorylated by PKA both in vitro and after cell pene- from the ability of MCa to convert RyR1 low-affinity ryanodine tration in cellulo. Unexpectedly, phosphorylation converts MCa binding sites into high-affinity sites, increase RyR1 sensitivity to + from positive to negative RyR1 allosteric modulator. Thr26 phos- activating low Ca2 concentrations (μM), and decrease RyR1 + phorylation leads to charge neutralization of Arg24, a residue sensitivity to inhibiting high Ca2 concentrations (mM), with the crucial for MCa agonist activity. The functional effect of Thr26 two latest effects probably requiring an allosteric mechanism. + phosphorylation is partially mimicked by aspartyl mutation. This MCa binding onto RyR1 also induces Ca2 release from sarco- represents the first case, to our knowledge, of both ex situ post- plasmic reticulum vesicles (8). These effects correlate with the translational modification and pharmacological reprogramming of induction by MCa of long-lasting subconductance open transi- a small natural cystine-rich peptide by target cells. So far, phos- tions of purified RyR1 channels reconstituted in artificial lipid phorylated MCa is the first specific negative allosteric modulator bilayers (7, 17, 18). This positive allosteric activity of MCa is the of RyR1, to our knowledge, and represents a lead compound for consequence of its interaction with a cytoplasmic RyR1 domain further development of phosphatase-resistant analogs. that directly controls the gating of this calcium channel (19). Production of MCa analogs after alanine scanning helped iden- maurocalcin | phosphorylation | pharmacology | toxin | ryanodine receptor tifying critical residues involved in the positive allosteric activity of the peptide (9, 20). The pharmacophore of MCa was re- 24 nimal venoms represent biolibraries that are natural sources stricted to a few basic amino acid residues, among which Arg Afor the discovery of a growing number of peptides with im- portant pharmacological properties. These peptides have been in- Significance strumental in discriminating different subtypes of ion channels and – membrane receptors (1 3). Several of them are now approved by Animal toxin peptides typically exhibit high affinity and selec- the US Food and Administration for the treatment of various hu- tivity for specific subclasses of cell receptors that account for man pathological conditions (4). Maurocalcin (MCa) is a 33-amino their activity. Posttranslational modifications of toxin sequences acid peptide that belongs to the family of the calcin toxins charac- may occur in the venom gland machinery, but there is no ex- terized by their folding forming an inhibitor cystine knot motif ample so far of toxins being subjected to such modifications ex (5, 6). After its initial purification from the venom of the scorpion situ after delivery to target cells. Here, we provide evidence that Scorpio maurus palmatus, MCa was obtained as a synthetic peptide the cell permeant maurocalcin (MCa), found in scorpion venom, that exhibits structural and pharmacological properties identical to undergoes PKA-mediated phosphorylation in cellulo, and that those of the natural peptide (7). Extensive characterization of MCa posttranslational modification leads to its complete pharmaco- identified it as one of the most potent effectors of ryanodine re- logical reprogramming activity toward ryanodine receptor type + ceptor type 1 (RyR1) (8, 9). RyR1 is one of the three isoforms that 1 (RyR1), a key player in Ca2 homeostasis in excitable cells. make up the RyR intracellular calcium channels family. It was first Phosphorylation converts MCa from a potent stabilizer of RyR1 identified in skeletal muscles (10) but is also broadly expressed in channel substates to a negative allosteric modulator that miti- 2+ many other tissues such as pre- and postsynaptic sites within neu- gates RyR1 channel Ca leak. + rons of the brain (11). RyR calcium channels regulate Ca2 release from intracellular stores, and therefore represent crucial players of Author contributions: M.R., I.N.P., and M.D.W. designed research; M.R., W.F., Y.D., S.A.K., V.V., S.C., H.D., and I.N.P. performed research; M.R., W.F., L.D., F.C.C., F.L., H.D., I.N.P., and a number of physiological and toxicological processes, from muscle M.D.W. analyzed data; and M.D.W. wrote the paper. contraction to gene expression (12). As a consequence, silencing of The authors declare no conflict of interest. the gene encoding RyR1 is lethal at birth (13). Despite extensive This article is a PNAS Direct Submission. studies of the RyR biophysical properties, only a few molecules 1M.R. and W.F. contributed equally to this work. specifically acting on these calcium channels have been identified. 2To whom correspondence may be addressed. Email: [email protected] or The only specific inhibitors of RyR1 known so far are ryanodine at [email protected]. high concentration (14), although this compound also exhibits ag- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. onist properties at low doses (15, 16), and dantrolene. Ruthenium 1073/pnas.1517342113/-/DCSupplemental. E2460–E2468 | PNAS | Published online April 11, 2016 www.pnas.org/cgi/doi/10.1073/pnas.1517342113 Downloaded by guest on October 1, 2021 was the most important for activity (9). Despite these extensive the first natural CPP, to our knowledge, emerging from venom PNAS PLUS studies, none of the mutations converted MCa into RyR1 antago- sources and whose cytoplasm delivery and activity could be straight- nist peptide, but mostly lowered affinity or inhibited agonist effect. forwardly examined through the activation of RyR channels (33). It It is highly unusual that a venom peptide targets an intracel- is therefore conceivable that MCa may undergo posttranslational lular receptor. Several reports indicate that MCa binds cell modifications by target cell enzymes on delivery into the cytoplasm. surface glycosaminoglycans (21) and membrane lipids (20), and In this report, we show that MCa is a substrate of PKA in vitro, that it rapidly translocates into cells using mechanisms akin to leading to the phosphorylation of Thr26. We also demonstrate cell-penetrating peptides (CPPs) (22). As a matter of fact, MCa that MCa phosphorylation happens in cellulo after translocation. and CPPs share interesting structural features, such as the pres- Phosphorylation of MCa leads to a fine peptide structural modi- ence of a strong dipole moment characterized by a heavily basic fication responsible for its complete pharmacological reprogram- face opposing a far less charged one (23–25), with the latter being ming, thereby converting MCa into a RyR1 antagonist. We thus also quite hydrophobic. Similar to a CPP, MCa proved to be ef- establish for the first time, to our knowledge, that the pharmaco- ficient in the transport of several types of cargoes ranging from logical properties of a small cell-penetrating toxin peptide can be drugs to peptides, proteins, and nanoparticles (22, 26–32). MCa is dramatically modified by posttranslational modification, opening A PKA consensus phosphorylation site RRXT S 123 MCa GDC1LPHLKLC2KENKDC3C4SKKC5KRRGTNIEKRC6R PHARMACOLOGY B MCa 4164.19 Da 50 b 26 40 MCab P-Thr 30 20 m/z 4170 10 0 16 18 20 22 Elution time (min) C 32P labelling Streptavidin-peroxidase 32 [ P]-MCab MCab Fig. 1. MCa is phosphorylated by PKA. (A) Identification of a consensus phosphorylation site in MCa primary structure. (B) In vitro phosphorylation of MCab by the catalytic subunit of PKA. Shift
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