title: Distinctive Properties of the Nuclear Localization Signals of Inner Nuclear Membrane Proteins Heh1 and Heh2.
abstract: Targeting of ER-synthesized membrane proteins to the inner nuclear membrane (INM) has long been explained by the diffusion-retention model. However, several INM proteins contain non-classical nuclear localization signal (NLS) sequences, which, in a few instances, have been shown to promote importin α/β- and Ran-dependent translocation to the INM. Here, using structural and biochemical methods, we show that yeast INM proteins Heh2 and Src1/Heh1 contain bipartite import sequences that associate intimately with the minor NLS-binding pocket of yeast importin α and unlike classical NLSs efficiently displace the IBB domain in the absence of importin β. In vivo, the intimate interactions at the minor NLS-binding pocket make the h2NLS highly efficient at recruiting importin α at the ER and drive INM localization of endogenous Heh2. Thus, h1/h2NLSs delineate a novel class of super-potent, IBB-like membrane protein NLSs, distinct from classical NLSs found in soluble cargos and of general interest in biology.
authors.affiliation: Dept. of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South 10 Street, Philadelphia, PA 19107, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Lokareddy
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.|Zernike Institute for Advanced Materials, Department of Biochemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, Netherlands.
authors.forename: Rizqiya A
authors.initials: RA
authors.lastname: Hapsari
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Mathilde
authors.initials: M
authors.lastname: van Rheenen
authors.affiliation: Dept. of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South 10 Street, Philadelphia, PA 19107, USA.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Pumroy
authors.affiliation: Dept. of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South 10 Street, Philadelphia, PA 19107, USA.
authors.forename: Anshul
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Steen
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Veenhoff
authors.affiliation: Dept. of Biochemistry and Molecular Biology, Thomas Jefferson University, 233 South 10 Street, Philadelphia, PA 19107, USA.
authors.forename: Gino
authors.initials: G
authors.lastname: Cingolani
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D001665:Binding Sites; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009685:Nuclear Envelope; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism
chemical_list: C556514:Heh2 protein, S cerevisiae; D008565:Membrane Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C532133:Src1 protein, S cerevisiae; D028961:beta Karyopherins