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- PDB-6cnn: Cryo-EM structure of the human SK4/calmodulin channel complex in ... -

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Basic information

Entry
Database: PDB / ID: 6cnn
TitleCryo-EM structure of the human SK4/calmodulin channel complex in the Ca2+ bound state I
Components
  • Calmodulin-1
  • Intermediate conductance calcium-activated potassium channel protein 4
KeywordsMEMBRANE PROTEIN / ion channel / neuroscience / calmodulin
Function / homology
Function and homology information


intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / stabilization of membrane potential / Ca2+ activated K+ channels / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / cell volume homeostasis ...intermediate conductance calcium-activated potassium channel activity / saliva secretion / small conductance calcium-activated potassium channel activity / stabilization of membrane potential / Ca2+ activated K+ channels / macropinocytosis / calcium-activated potassium channel activity / regulation of calcium ion import across plasma membrane / positive regulation of potassium ion transmembrane transport / cell volume homeostasis / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / phospholipid translocation / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / CaMK IV-mediated phosphorylation of CREB / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of calcium ion export across plasma membrane / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / presynaptic endocytosis / regulation of cardiac muscle cell action potential / positive regulation of ryanodine-sensitive calcium-release channel activity / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / positive regulation of T cell receptor signaling pathway / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of ryanodine-sensitive calcium-release channel activity / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / calcineurin-mediated signaling / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / Long-term potentiation / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / protein phosphatase activator activity / regulation of ryanodine-sensitive calcium-release channel activity / DARPP-32 events / immune system process / Smooth Muscle Contraction / catalytic complex / potassium channel activity / detection of calcium ion / regulation of cardiac muscle contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / presynaptic cytosol / calcium channel inhibitor activity / cellular response to interferon-beta / Protein methylation / Activation of AMPK downstream of NMDARs / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / regulation of calcium-mediated signaling / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / titin binding / voltage-gated potassium channel complex / potassium ion transmembrane transport / sperm midpiece / substantia nigra development / calcium channel complex / calyx of Held / FCERI mediated Ca+2 mobilization / Ras activation upon Ca2+ influx through NMDA receptor / FCGR3A-mediated IL10 synthesis / adenylate cyclase activator activity / regulation of heart rate / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / protein serine/threonine kinase activator activity / VEGFR2 mediated cell proliferation / sarcomere / regulation of cytokinesis / VEGFR2 mediated vascular permeability / positive regulation of protein secretion / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of receptor signaling pathway via JAK-STAT / spindle microtubule / establishment of localization in cell / RAF activation / Transcriptional activation of mitochondrial biogenesis / defense response / potassium ion transport / Stimuli-sensing channels / cellular response to type II interferon / long-term synaptic potentiation / ruffle membrane / response to calcium ion
Similarity search - Function
Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / EF-hand / : ...Calmodulin-binding domain / Potassium channel, calcium-activated, SK / SK, calmodulin-binding domain superfamily / Calmodulin binding domain / Calcium-activated SK potassium channel / Calmodulin binding domain / Potassium channel domain / Ion channel / EF-hand / : / Recoverin; domain 1 / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
: / Chem-POV / Intermediate conductance calcium-activated potassium channel protein 4 / Calmodulin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLee, C.H. / MacKinnon, R.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)GM43949 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Science / Year: 2018
Title: Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures.
Authors: Chia-Hsueh Lee / Roderick MacKinnon /
Abstract: Small-conductance Ca-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 ...Small-conductance Ca-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-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.
History
DepositionMar 8, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 2, 2018Provider: repository / Type: Initial release
Revision 1.0May 2, 2018Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.0May 2, 2018Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 2, 2018Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0May 2, 2018Data content type: Additional map / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0May 2, 2018Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 2, 2018Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0May 2, 2018Data content type: Additional map / Data content type: Additional map / Provider: repository / Type: Initial release
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Revision 1.0May 2, 2018Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 23, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Revision 1.4May 14, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 14, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
A: Intermediate conductance calcium-activated potassium channel protein 4
B: Intermediate conductance calcium-activated potassium channel protein 4
C: Intermediate conductance calcium-activated potassium channel protein 4
D: Intermediate conductance calcium-activated potassium channel protein 4
E: Calmodulin-1
F: Calmodulin-1
G: Calmodulin-1
H: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)266,20736
Polymers258,4448
Non-polymers7,76328
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area43080 Å2
ΔGint-275 kcal/mol
Surface area101580 Å2

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Components

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Protein , 2 types, 8 molecules ABCDEFGH

#1: Protein
Intermediate conductance calcium-activated potassium channel protein 4 / SK4 channel / SKCa4 / IKCa1 / IK1 / KCa3.1 / KCa4 / Putative Gardos channel


Mass: 47758.496 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNN4, IK1, IKCA1, KCA4, SK4 / Production host: Homo sapiens (human) / References: UniProt: O15554
#2: Protein
Calmodulin-1


Mass: 16852.545 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Homo sapiens (human) / References: UniProt: P0DP23

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Sugars , 1 types, 8 molecules

#5: Sugar
ChemComp-LMT / DODECYL-BETA-D-MALTOSIDE


Type: D-saccharide / Mass: 510.615 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C24H46O11 / Comment: detergent*YM

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Non-polymers , 3 types, 20 molecules

#3: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: K
#4: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#6: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca

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Details

Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human SK4/calmodulin channel complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 75 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.12_2829: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 91511 / Symmetry type: POINT
RefinementHighest resolution: 3.5 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.02216111
ELECTRON MICROSCOPYf_angle_d0.87921608
ELECTRON MICROSCOPYf_dihedral_angle_d15.3219408
ELECTRON MICROSCOPYf_chiral_restr0.052544
ELECTRON MICROSCOPYf_plane_restr0.0062668

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