title: The structure and regulation of human muscle α-actinin.
abstract: The spectrin superfamily of proteins plays key roles in assembling the actin cytoskeleton in various cell types, crosslinks actin filaments, and acts as scaffolds for the assembly of large protein complexes involved in structural integrity and mechanosensation, as well as cell signaling. α-actinins in particular are the major actin crosslinkers in muscle Z-disks, focal adhesions, and actin stress fibers. We report a complete high-resolution structure of the 200 kDa α-actinin-2 dimer from striated muscle and explore its functional implications on the biochemical and cellular level. The structure provides insight into the phosphoinositide-based mechanism controlling its interaction with sarcomeric proteins such as titin, lays a foundation for studying the impact of pathogenic mutations at molecular resolution, and is likely to be broadly relevant for the regulation of spectrin-like proteins.
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Euripedes de Almeida
authors.initials: Ede A
authors.lastname: Ribeiro
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Nikos
authors.initials: N
authors.lastname: Pinotsis
authors.affiliation: British Heart Foundation Centre of Research Excellence, Randall Division for Cell and Molecular Biophysics and Cardiovascular Division, King's College London, London SE1 1UL, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghisleni
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Anita
authors.initials: A
authors.lastname: Salmazo
authors.affiliation: European Molecular Biology Laboratory, Deutsches Elektronen-Synchrotron, Notkestrasse 85, 22603 Hamburg, Germany.
authors.forename: Petr V
authors.initials: PV
authors.lastname: Konarev
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Julius
authors.initials: J
authors.lastname: Kostan
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Björn
authors.initials: B
authors.lastname: Sjöblom
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schreiner
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria; M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia.
authors.forename: Anton A
authors.initials: AA
authors.lastname: Polyansky
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Eirini A
authors.initials: EA
authors.lastname: Gkougkoulia
authors.affiliation: British Heart Foundation Centre of Research Excellence, Randall Division for Cell and Molecular Biophysics and Cardiovascular Division, King's College London, London SE1 1UL, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Holt
authors.affiliation: Department of Biotechnology, Norwegian University of Science and Technology, Sem Sælands vei 6/8, 7491 Trondheim, Norway.
authors.forename: Finn L
authors.initials: FL
authors.lastname: Aachmann
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Bojan
authors.initials: B
authors.lastname: Zagrović
authors.affiliation: Laboratory of Physical Chemistry, ETH Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland; Fachbereich Physik, Freie Universität Berlin, Arnimallee 14, 14195 Berlin, Germany.
authors.forename: Enrica
authors.initials: E
authors.lastname: Bordignon
authors.affiliation: Division of Biochemistry, Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna, Austria.
authors.forename: Katharina F
authors.initials: KF
authors.lastname: Pirker
authors.affiliation: European Molecular Biology Laboratory, Deutsches Elektronen-Synchrotron, Notkestrasse 85, 22603 Hamburg, Germany.
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.affiliation: British Heart Foundation Centre of Research Excellence, Randall Division for Cell and Molecular Biophysics and Cardiovascular Division, King's College London, London SE1 1UL, UK. Electronic address: mathias.gautel@kcl.ac.uk.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gautel
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria; Department of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia. Electronic address: kristina.djinovic@univie.ac.at.
authors.forename: Kristina
authors.initials: K
authors.lastname: Djinović-Carugo
mesh_terms: D000185:Actinin / Q000737:chemistry*; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D016415:Sequence Alignment; D014961:X-Ray Diffraction
chemical_list: C401401:ACTN2 protein, human; D008024:Ligands; D000185:Actinin