Dynorphin A induces membrane permeabilization by formation of proteolipidic pores. Insights from electrophysiology and computational simulations
Perini, D. Aurora (Laboratory of Molecular Biophysics. Department of Physics. Universitat Jaume I)
Aguilella-Arzo, Marcel (Laboratory of Molecular Biophysics. Department of Physics. Universitat Jaume I)
Alcaraz, Antonio (Laboratory of Molecular Biophysics. Department of Physics. Universitat Jaume I)
Perálvarez-Marín, Alex (Universitat Autònoma de Barcelona. Institut de Neurociències)
Queralt-Martín, María (Laboratory of Molecular Biophysics. Department of Physics. Universitat Jaume I)

Date:	2021
Abstract:	Dynorphins are endogenous neuropeptides that function as ligands for the κ-opioid receptor. In addition to opioid activity, dynorphins can induce several pathological effects such as neurological dysfunctions and cell death. Previous studies have suggested that Dynorphin A (DynA) mediates some pathogenic actions through formation of transient pores in lipid domains of the plasma membrane. Here, we use planar bilayer electrophysiology to show that DynA induces pore formation in negatively charged membranes. We find a large variability in pore conformations showing equilibrium conductance fluctuations, what disregards electroporation as the dominant mechanism of pore formation. Ion selectivity measurements showing cationic selectivity indicate that positive protein charges of DynA are stabilized by phosphatidyl serine negative charges in the formation of combined structures. We complement our study with computational simulations that assess the stability of diverse peptide arrangements in the hydrophobic core of the bilayer. We show that DynA is capable of assembling in charged membranes to form water-filled pores that conduct ions.
Grants:	Agencia Estatal de Investigación 2019-108434GB-I00 Agencia Estatal de Investigación IJC2018-035283-I Agencia Estatal de Investigación 2020-120222GB-I00
Note:	Altres ajuts: Universitat Jaume I (UJI-B2018-53; UJI-A2020-21) i Generalitat Valenciana (GRISOLIAP/2018/061; AICO/2020/066)
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Dynorphin ; Membrane permeabilization ; Ion channel ; Noise and fluctuations ; Protein-lipid interactions ; Proteolipidic pores ; Computational simulations
Published in:	Computational and Structural Biotechnology Journal, Vol. 20 (december 2021) , p. 230-240, ISSN 2001-0370

DOI: 10.1016/j.csbj.2021.12.021
PMID: 35024095

11 p, 4.9 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles