title: Contribution of the central hydrophobic residue in the PXP motif of voltage-dependent K+ channels to S6 flexibility and gating properties.
abstract: Shaker-like (KV1.1) channels contain a highly conserved Pro-Val-Pro (PVP) motif at the base of S6 that produces a kink in the S6 helices and provides a flexible element thought to be essential for channel gating. The role of proline-induced kinks in transmembrane helices is well known, but the contribution of the small hydrophobic valine between these two prolines is not known, and interestingly, Shab-like (KV2.1) channels possess an isoleucine at this position (PIP). Here we show that the exact nature of this central hydrophobic residue within the PXP motif confers unique functional properties to KV1 channels, including changes in activation and deactivation kinetics, voltage-dependent properties and open probabilities, but single-channel conductance and cell expression levels are not affected. In support of these functional changes, molecular dynamic simulations demonstrate that valine and isoleucine contribute differently to S6 flexibility within this motif. These results therefore indicate that the nature of the central hydrophobic residue in the PXP motif is an important functional determinant of KV channel gating by contributing, at least in part, to the relative flexibility of this motif.
authors.affiliation: Section of Human Physiology, Department of Internal Medicine, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Imbrici
authors.forename: Alessandro
authors.initials: A
authors.lastname: Grottesi
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: D'Adamo
authors.forename: Roberta
authors.initials: R
authors.lastname: Mannucci
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
authors.forename: Mauro
authors.initials: M
authors.lastname: Pessia
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating; D007532:Isoleucine; D007700:Kinetics; D051662:Kv1.1 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes; D011188:Potassium / Q000378:metabolism*; D011487:Protein Conformation; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014633:Valine; D014982:Xenopus laevis
chemical_list: C496946:KCNA1 protein, human; D007532:Isoleucine; D051662:Kv1.1 Potassium Channel; D014633:Valine; D011188:Potassium