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Volume 20
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10.3390/ijms20051021
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Article

The HslV Protease from Leishmania major and Its Activation by C-terminal HslU Peptides

by
Ndeye Mathy Kebe
1,
Krishnananda Samanta
2,†,
Priyanka Singh
2,†,
Joséphine Lai-Kee-Him
3,4,
Viviana Apicella
2,
Nadine Payrot
2,
Noémie Lauraire
1,
Baptiste Legrand
2,
Vincent Lisowski
2,
Diane-Ethna Mbang-Benet
5,
Michel Pages
5,‡,
Patrick Bastien
5,
Andrey V. Kajava
1,6,
Patrick Bron
3,4,
Jean-François Hernandez
2,* and
Olivier Coux
1,*
1
Centre de Recherche en Biologie cellulaire de Montpellier (CRBM), CNRS, Université de Montpellier, 34090 Montpellier, France
2
Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 34090 Montpellier, France
3
Centre de Biochimie Structurale (CBS), INSERM, CNRS, Université de Montpellier, 34090 Montpellier, France
4
PIBBS, Biocampus Montpellier, CNRS, INSERM, Université de Montpellier, 34000 Montpellier, France
5
Laboratory of Parasitology-Mycology, MIVEGEC, CNRS, IRD, Université de Montpellier, 34000 Montpellier, France
6
Institut de Biologie Computationnelle, Université de Montpellier, 34000 Montpellier, France
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
In memoriam.
Int. J. Mol. Sci. 2019, 20(5), 1021; https://doi.org/10.3390/ijms20051021
Received: 11 January 2019 / Revised: 11 February 2019 / Accepted: 20 February 2019 / Published: 26 February 2019
(This article belongs to the Section Biochemistry)
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Abstract

HslVU is an ATP-dependent proteolytic complex present in certain bacteria and in the mitochondrion of some primordial eukaryotes, including deadly parasites such as Leishmania. It is formed by the dodecameric protease HslV and the hexameric ATPase HslU, which binds via the C-terminal end of its subunits to HslV and activates it by a yet unclear allosteric mechanism. We undertook the characterization of HslV from Leishmania major (LmHslV), a trypanosomatid that expresses two isoforms for HslU, LmHslU1 and LmHslU2. Using a novel and sensitive peptide substrate, we found that LmHslV can be activated by peptides derived from the C-termini of both LmHslU1 and LmHslU2. Truncations, Ala- and D-scans of the C-terminal dodecapeptide of LmHslU2 (LmC12-U2) showed that five out of the six C-terminal residues of LmHslU2 are essential for binding to and activating HslV. Peptide cyclisation with a lactam bridge allowed shortening of the peptide without loss of potency. Finally, we found that dodecapeptides derived from HslU of other parasites and bacteria are able to activate LmHslV with similar or even higher efficiency. Importantly, using electron microscopy approaches, we observed that the activation of LmHslV was accompanied by a large conformational remodeling, which represents a yet unidentified layer of control of HslV activation. View Full-Text
Keywords: ATP-dependent protease; HslVU; peptide chemical synthesis; cryo-electron microscopy; Leishmania; mitochondria; allosteric regulation; cyclic peptides ATP-dependent protease; HslVU; peptide chemical synthesis; cryo-electron microscopy; Leishmania; mitochondria; allosteric regulation; cyclic peptides
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MDPI and ACS Style

Kebe, N.M.; Samanta, K.; Singh, P.; Lai-Kee-Him, J.; Apicella, V.; Payrot, N.; Lauraire, N.; Legrand, B.; Lisowski, V.; Mbang-Benet, D.-E.; Pages, M.; Bastien, P.; Kajava, A.V.; Bron, P.; Hernandez, J.-F.; Coux, O. The HslV Protease from Leishmania major and Its Activation by C-terminal HslU Peptides. Int. J. Mol. Sci. 2019, 20, 1021. https://doi.org/10.3390/ijms20051021

AMA Style

Kebe NM, Samanta K, Singh P, Lai-Kee-Him J, Apicella V, Payrot N, Lauraire N, Legrand B, Lisowski V, Mbang-Benet D-E, Pages M, Bastien P, Kajava AV, Bron P, Hernandez J-F, Coux O. The HslV Protease from Leishmania major and Its Activation by C-terminal HslU Peptides. International Journal of Molecular Sciences. 2019; 20(5):1021. https://doi.org/10.3390/ijms20051021

Chicago/Turabian Style

Kebe, Ndeye M., Krishnananda Samanta, Priyanka Singh, Joséphine Lai-Kee-Him, Viviana Apicella, Nadine Payrot, Noémie Lauraire, Baptiste Legrand, Vincent Lisowski, Diane-Ethna Mbang-Benet, Michel Pages, Patrick Bastien, Andrey V. Kajava, Patrick Bron, Jean-François Hernandez, and Olivier Coux. 2019. "The HslV Protease from Leishmania major and Its Activation by C-terminal HslU Peptides" International Journal of Molecular Sciences 20, no. 5: 1021. https://doi.org/10.3390/ijms20051021

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