Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures

• Published in: Science (American Association for the Advancement of Science) Vol. 360; no. 6388; pp. 508 - 513
• Main Authors: Lee, Chia-Hsueh, MacKinnon, Roderick
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 04.05.2018
• Subjects: Acetamides - chemistry; Activation; Anatomy; Blood cells; Calcium; Calcium (intracellular); Calcium channels; Calcium conductance; Calcium ions; Calcium-binding protein; Calmodulin; Calmodulin - agonists; Calmodulin - chemistry; Calmodulin - ultrastructure; Channel gating; Channels; Cryoelectron Microscopy; Electron microscopy; Excitability; Helices; Humans; Immune response; Intermediate-Conductance Calcium-Activated Potassium Channels - agonists; Intermediate-Conductance Calcium-Activated Potassium Channels - chemistry; Intermediate-Conductance Calcium-Activated Potassium Channels - ultrastructure; Molecular biology; Nervous system; Pharmacology; Potassium; Potassium Channel Blockers - chemistry; Potassium channels; Potassium channels (calcium-gated); Potassium conductance; Protein Domains; Proteins; Resistance; Synaptic plasticity; Synaptic transmission; Thiazines - chemistry; Transmission electron microscopy; Triphenylmethyl Compounds - chemistry
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aas9466

Small-conductance Ca 2+ -activated K + (SK) channels are expressed throughout the nervous system and affect both the intrinsic excitability of neurons and synaptic transmission. An increase in the concentration of intracellular calcium opens the channels to conduct potassium across the cell membrane. Lee and MacKinnon report cryo–electron microscopy structures of human SK4-calmodulin channel complexes. Activation occurs when calcium binds to calmodulin, a protein with two lobes, known as C and N, separated by a flexible region. Each monomer in the channel tetramer binds constitutively to the C-lobe of calmodulin. The N-lobe of calmodulin is reasonably unconstrained until it binds calcium. With calcium bound, it then binds to the channel and induces conformational changes that open the pore. Science , this issue p. 508 Structural insights into how Ca 2+ -bound calmodulin activates the small-conductance Ca 2+ -activated K + channel for neuronal excitation are explored. Small-conductance Ca 2+ -activated K + (SK) channels mediate neuron excitability and are associated with synaptic transmission and plasticity. They also regulate immune responses and the size of blood cells. Activation of SK channels requires calmodulin (CaM), but how CaM binds and opens SK channels has been unclear. Here we report cryo–electron microscopy (cryo-EM) structures of a human SK4-CaM channel complex in closed and activated states at 3.4- and 3.5-angstrom resolution, respectively. Four CaM molecules bind to one channel tetramer. Each lobe of CaM serves a distinct function: The C-lobe binds to the channel constitutively, whereas the N-lobe interacts with the S4-S5 linker in a Ca 2+ -dependent manner. The S4-S5 linker, which contains two distinct helices, undergoes conformational changes upon CaM binding to open the channel pore. These structures reveal the gating mechanism of SK channels and provide a basis for understanding SK channel pharmacology.