title: Interaction of calmodulin with Sec61α limits Ca2+ leakage from the endoplasmic reticulum.
abstract: In eukaryotes, protein transport into the endoplasmic reticulum (ER) is facilitated by a protein-conducting channel, the Sec61 complex. The presence of large, water-filled pores with uncontrolled ion permeability, as formed by Sec61 complexes in the ER membrane, would seriously interfere with the regulated release of calcium from the ER lumen into the cytosol, an essential mechanism for intracellular signalling. We identified a calmodulin (CaM)-binding motif in the cytosolic N-terminus of mammalian Sec61α that bound CaM but not Ca2+-free apocalmodulin with nanomolar affinity and sequence specificity. In single-channel measurements, CaM potently mediated Sec61-channel closure in Ca2+-dependent manner. At the cellular level, two different CaM antagonists stimulated calcium release from the ER through Sec61 channels. However, protein transport into microsomes was not modulated by Ca2+-CaM. Molecular modelling of the ribosome/Sec61/CaM complexes supports the view that simultaneous ribosome and CaM binding to the Sec61 complex may be possible. Overall, CaM is involved in limiting Ca2+ leakage from the ER.
authors.affiliation: Biophysics, Osnabrück University, Osnabrück, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Erdmann
authors.forename: Nico
authors.initials: N
authors.lastname: Schäuble
authors.forename: Sven
authors.initials: S
authors.lastname: Lang
authors.forename: Martin
authors.initials: M
authors.lastname: Jung
authors.forename: Alf
authors.initials: A
authors.lastname: Honigmann
authors.forename: Mazen
authors.initials: M
authors.lastname: Ahmad
authors.forename: Johanna
authors.initials: J
authors.lastname: Dudek
authors.forename: Julia
authors.initials: J
authors.lastname: Benedix
authors.forename: Anke
authors.initials: A
authors.lastname: Harsman
authors.forename: Annika
authors.initials: A
authors.lastname: Kopp
authors.forename: Volkhard
authors.initials: V
authors.lastname: Helms
authors.forename: Adolfo
authors.initials: A
authors.lastname: Cavalié
authors.forename: Richard
authors.initials: R
authors.lastname: Wagner
authors.forename: Richard
authors.initials: R
authors.lastname: Zimmermann
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D008969:Molecular Sequence Data; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport; D000069816:SEC Translocation Channels; D019596:Wolves / Q000378:metabolism
chemical_list: D002147:Calmodulin; D008565:Membrane Proteins; D021122:Protein Subunits; D000069816:SEC Translocation Channels; D002118:Calcium