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Structure/Function relationships in membrane proteins: Neuroreceptors and ion channels. Lipid-Protein and Protein-Protein interactions in biological membranes. Modulation of ion channels. Potential applications to drug discovery.


J Biol Chem. 2015 Oct 16;290(42):25745-55. doi: 10.1074/jbc.M115.669598. Epub 2015 Sep 2. Competing Lipid-Protein and Protein-Protein Interactions Determine Clustering and Gating Patterns in the Potassium Channel from Streptomyces lividans (KcsA). Molina ML, Giudici AM, Poveda JA, Fernández-Ballester G, Montoya E, Renart ML, Fernández AM, Encinar JA, Riquelme G, Morales A, González-Ros JM

There is increasing evidence to support the notion that membrane proteins, instead of being isolated components floating in a fluid lipid environment, can be assembled into supramolecular complexes that take part in a variety of cooperative cellular functions. The interplay between lipid-protein and protein-protein interactions is expected to be a determinant factor in the assembly and dynamics of such membrane complexes. Here we report on a role of anionic phospholipids in determining the extent of clustering of KcsA, a model potassium channel. Assembly/disassembly of channel clusters occurs, at least partly, as a consequence of competing lipid-protein and protein-protein interactions at nonannular lipid binding sites on the channel surface and brings about profound changes in the gating properties of the channel. Our results suggest that these latter effects of anionic lipids are mediated via the Trp(67)-Glu(71)-Asp(80) inactivation triad within the channel structure and its bearing on the selectivity filter.

Biochemistry. 2012 May 8;51(18):3891-900. doi: 10.1021/bi201497n. Epub 2012 Apr 27. Contribution of ion binding affinity to ion selectivity and permeation in KcsA, a model potassium channel. Renart ML, Montoya E, Fernández AM, Molina ML, Poveda JA, Encinar JA, Ayala JL, Ferrer-Montiel AV, Gómez J, Morales A, González Ros JM.

Ion permeation and selectivity, key features in ion channel function, are believed to arise from a complex ensemble of energetic and kinetic variables. Here we evaluate the contribution of pore cation binding to ion permeation and selectivity features of KcsA, a model potassium channel. For this, we used E71A and M96V KcsA mutants in which the equilibrium between conductive and nonconductive conformations of the channel is differently shifted. E71A KcsA is a noninactivating channel mutant. Binding of K+ to this mutant reveals a single set of low-affinity K+ binding sites, similar to that seen in the binding of K+ to wild-type KcsA that produces a conductive, low-affinity complex. This seems consistent with the observed K+ permeation in E71A. Nonetheless, the E71A mutant retains K+ selectivity, which cannot be explained on the basis of just its low affinity for this ion. At variance, M96V KcsA is a rapidly inactivating mutant that has lost selectivity for K+ and also conducts Na+. Here, low-affinity binding and high-affinity binding of both cations are detected, seemingly in agreement with both being permeating species in this mutant channel. In conclusion, binding of the ion to the channel protein seemingly explains certain gating, ion selectivity, and permeation properties. Ion binding stabilizes greatly the channel and, depending upon ion type and concentration, leads to different conformations and ion binding affinities. High-affinity states guarantee binding of specific ions and mediate ion selectivity but are nonconductive. Conversely, low-affinity states would not discriminate well among different ions but allow permeation to occur.


José Manuel González-Ros

José Antonio Poveda Larrosa


Mª Lourdes Renart Pérez

Marcela Giucici


Estefanía Montoya Díaz


Eva María Martínez Martínez


  1. Biochim Biophys Acta. 2014 Jun;1838(6):1560-7. doi: 10.1016/j.bbamem.2013.10.023. Epub 2013 Nov 8. Lipid modulation of ion channels through specific binding sites. Poveda JA, Giudici AM, Renart ML, Molina ML, Montoya E, Fernández-Carvajal A, Fernández-Ballester G, Encinar JA, González-Ros JM.
  2. Biochim Biophys Acta. 2013 Feb;1828(2):193-200. doi: 10.1016/j.bbamem.2012.09.020. Epub 2012 Sep 27. Detergent-labile, supramolecular assemblies of KcsA: relative abundance and interactions involved. Giudici AM, Molina ML, Ayala JL, Montoya E, Renart ML, Fernández AM, Encinar JA, Ferrer-Montiel AV, Poveda JA, González-Ros JM.
  3. PLoS One. 2011;6(10):e25529. doi: 10.1371/journal.pone.0025529. Epub 2011 Oct 6. Functional reconstitution of a voltage-gated potassium channel in giant unilamellar vesicles. Aimon S, Manzi J, Schmidt D, Poveda Larrosa JA, Bassereau P, Toombes GE.
  4. Biochemistry. 2010 Nov 9;49(44):9480-7. doi: 10.1021/bi101235v. Ion binding to KcsA: implications in ion selectivity and channel gating. Renart ML1, Triano I, Poveda JA, Encinar JA, Fernández AM, Ferrer-Montiel AV, Gómez J, González Ros JM.
  5. Biochemistry. 2010 Jun 29;49(25):5397-404. doi: 10.1021/bi1003712. Occupancy of nonannular lipid binding sites on KcsA greatly increases the stability of the tetrameric protein. Triano I, Barrera FN, Renart ML, Molina ML, Fernández-Ballester G, Poveda JA, Fernández AM, Encinar JA, Ferrer-Montiel AV, Otzen D, González-Ros JM.
  6. J Phys Chem B. 2009 May 28;113(21):7534-40. doi: 10.1021/jp9019443. Biophysical and functional characterization of an ion channel peptide confined in a sol-gel matrix. Esquembre R, Poveda JA, Mateo CR.
  7. J Biol Chem. 2008 Jun 27;283(26):18076-85. doi: 10.1074/jbc.M710132200. Epub 2008 Apr 22. N-type inactivation of the potassium channel KcsA by the Shaker B "ball" peptide: mapping the inactivating peptide-binding epitope. Molina ML, Barrera FN, Encinar JA, Renart ML, Fernández AM, Poveda JA, Santoro J, Bruix M, Gavilanes F, Fernández-Ballester G, Neira JL, González-Ros JM.


1) Inventores: Francisco Barcelo Gomila, Antonio Roig Muntaner, Jose R. Tomás Justribo, José M. González-Ros. Titulo: "A device for administration of medication by iontophoresis for local-regional treatment.". Titular: C.I.T. Ionophor S.L. Registros: Patente Europea número 90100236.0. Año 1995.

2) Inventores: Antonio Ferrer Montiel, Carlos Belmonte Martínez, Enrique Pérez Payá, Juana Gallar Martínez, José Manuel González Ros, Maria Remedios Galiana Gregori, Rosa Maria Planells Cases. Titulo: "Péptidos Capaces De Bloquear La Respuesta A Sustancias Químicas O Estímulos Térmicos O Mediadores De La Inflamación De Los Nociceptores, Y Composiciones Farmacéuticas Que Los Contienen". Titular: Universidad Miguel Hernández De Elche. Registros: Es2, 159, 463; Wo00/56, 761; Ep1, 179, 538. Año 2002.

3) Inventores: Antonio Ferrer-Montiel, Rosa Planells Cases, Carolina García Martínez, José Manuel González Ros, Jaime M Merino Fernández, Carlos Belmonte Martínez, Juana Gallar Martínez, Enrique Pérez Payá, Francisco Sánchez Baeza, Marc Humet, Angel Messeguer Peypoch. Titulo: "Trímeros de N-alquilglicina capaces de bloquear la respuesta a sustancias químicas, estímulos térmicos o mediadores de la inflamación de receptores neuronales, y composiciones que los contienen". Titular: DiverDrugs, SL. Registros: ES2169691 B1 (concesión 16/03/2004); WO02/30956; EP1338605 A1; US2004/33958; AU9388201; BR200114802 A; CA2425520 A1; JP2004/511491; MX PA/a/03003158.

4) Inventores: Antonio Ferrer‑Montiel, Asia Fernández-Carvajal, Gregorio Fernandez Ballester, José Manuel González Ros, Carlos Belmonte Martínez, Félix Viana, Ana Gomis, Pierluigi Valente y María Camprubí-Robles. Titulo: "Péptidos inhibidores de los termorreceptores". Titular: UMH (50%), DiverDrugs (40%), CSIC (10%). Registros: En fase de escritura. ABG Patents.

5) Inventores: Antonio Ferrer‑Montiel, Asia Fernández-Carvajal, Gregorio Fernandez Ballester, José Manuel González Ros, Carlos Belmonte Martínez, Félix Viana, Ana Gomis, Rosa María Planells-Cases, Miquel Vidal, Jordi Bujons, Angel Messeguer. Titulo: "Compuestos inhibidores de los termorreceptores". Titular: UMH (33%), CSIC (33%), CIPF (33%). Registros: En fase de escritura. ABG Patents