title: Structure of Dimeric and Tetrameric Complexes of the BAR Domain Protein PICK1 Determined by Small-Angle X-Ray Scattering.
abstract: PICK1 is a neuronal scaffolding protein containing a PDZ domain and an auto-inhibited BAR domain. BAR domains are membrane-sculpting protein modules generating membrane curvature and promoting membrane fission. Previous data suggest that BAR domains are organized in lattice-like arrangements when stabilizing membranes but little is known about structural organization of BAR domains in solution. Through a small-angle X-ray scattering (SAXS) analysis, we determine the structure of dimeric and tetrameric complexes of PICK1 in solution. SAXS and biochemical data reveal a strong propensity of PICK1 to form higher-order structures, and SAXS analysis suggests an offset, parallel mode of BAR-BAR oligomerization. Furthermore, unlike accessory domains in other BAR domain proteins, the positioning of the PDZ domains is flexible, enabling PICK1 to perform long-range, dynamic scaffolding of membrane-associated proteins. Together with functional data, these structural findings are compatible with a model in which oligomerization governs auto-inhibition of BAR domain function.
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute 18.6, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Morten L
authors.initials: ML
authors.lastname: Karlsen
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute 18.6, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Thor S
authors.initials: TS
authors.lastname: Thorsen
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, Room E-509, 1300 York Avenue, 10065, New York City, NY, USA.
authors.forename: Niklaus
authors.initials: N
authors.lastname: Johner
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute 18.6, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Ina
authors.initials: I
authors.lastname: Ammendrup-Johnsen
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute 18.6, University of Copenhagen, 2200 Copenhagen N, Denmark.|Structural Biology and NMR Laboratory, Department of Biology, Faculty of Science, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Erlendsson
authors.affiliation: Biostructural Research, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Xinsheng
authors.initials: X
authors.lastname: Tian
authors.affiliation: Structural Biophysics, Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen Ø, Denmark.
authors.forename: Jens B
authors.initials: JB
authors.lastname: Simonsen
authors.affiliation: Structural Biophysics, Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen Ø, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Høiberg-Nielsen
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute 18.6, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Nikolaj M
authors.initials: NM
authors.lastname: Christensen
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, Room E-509, 1300 York Avenue, 10065, New York City, NY, USA.
authors.forename: George
authors.initials: G
authors.lastname: Khelashvili
authors.affiliation: NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: Werner
authors.initials: W
authors.lastname: Streicher
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, Faculty of Science, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Teilum
authors.affiliation: Biostructural Research, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Vestergaard
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, Room E-509, 1300 York Avenue, 10065, New York City, NY, USA.
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute 18.6, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gether
authors.affiliation: Structural Biophysics, Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen Ø, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Arleth
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, The Panum Institute 18.6, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Madsen
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry*; D002522:Chlorocebus aethiops; D006801:Humans; D056004:Molecular Dynamics Simulation; D009687:Nuclear Proteins / Q000737:chemistry*; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D012996:Solutions; D014961:X-Ray Diffraction
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C498297:PICk1 protein, human; D012996:Solutions; D002118:Calcium