title: Karyopherin-mediated import of integral inner nuclear membrane proteins.
abstract: Targeting of newly synthesized integral membrane proteins to the appropriate cellular compartment is specified by discrete sequence elements, many of which have been well characterized. An understanding of the signals required to direct integral membrane proteins to the inner nuclear membrane (INM) remains a notable exception. Here we show that integral INM proteins possess basic sequence motifs that resemble 'classical' nuclear localization signals. These sequences can mediate direct binding to karyopherin-alpha and are essential for the passage of integral membrane proteins to the INM. Furthermore, karyopherin-alpha, karyopherin-beta1 and the Ran GTPase cycle are required for INM targeting, underscoring parallels between mechanisms governing the targeting of integral INM proteins and soluble nuclear transport. We also provide evidence that specific nuclear pore complex proteins contribute to this process, suggesting a role for signal-mediated alterations in the nuclear pore complex to allow for passage of INM proteins along the pore membrane.
authors.affiliation: Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA. mking@rockefeller.edu
authors.forename: Megan C
authors.initials: MC
authors.lastname: King
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Lusk
authors.forename: Günter
authors.initials: G
authors.lastname: Blobel
mesh_terms: D020816:Amino Acid Motifs; D020558:GTP Phosphohydrolases / Q000378:metabolism; D028884:Karyopherins / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D019913:Nuclear Localization Signals; D022022:Nuclear Pore / Q000737:chemistry / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D028884:Karyopherins; D008565:Membrane Proteins; C097178:NUP170 protein, S cerevisiae; C400753:NUP2 protein, S cerevisiae; D019913:Nuclear Localization Signals; D028861:Nuclear Pore Complex Proteins; D029701:Saccharomyces cerevisiae Proteins; D020558:GTP Phosphohydrolases; D020931:ran GTP-Binding Protein