title: Allosteric Regulation in Gating the Central Channel of the Nuclear Pore Complex.
abstract: The nuclear pore complex (NPC) arose in evolution as the cell's largest and most versatile transport channel. Current models for selective transport mediated by NPCs are focused on properties of intrinsically disordered regions of nucleoporins that bind transport factors. In contrast, structured regions are considered to provide static anchoring sites for the disordered regions without affecting transport factor binding. Here, we demonstrate allosteric coupling between a structured domain of a channel nucleoporin (Nup58) and its neighboring disordered domain in interaction with another channel nucleoporin (Nup54) and a transport factor (Kapβ1). Analysis of multiple equilibria showed that multivalent interactions of Kapβ1 with the disordered domains of Nup58 stabilize the neighboring structured domain associated with Nup54, shifting conformational equilibria from homo-oligomers to hetero-oligomers. Based on these and previous crystallographic results, a quantitative framework was established to describe constriction and dilation of the central channel as a function of transport factor occupancy.
authors.affiliation: Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: jkoh@rockefeller.edu.
authors.forename: Junseock
authors.initials: J
authors.lastname: Koh
authors.affiliation: Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: blobel@rockefeller.edu.
authors.forename: Günter
authors.initials: G
authors.lastname: Blobel
mesh_terms: D021581:Active Transport, Cell Nucleus; D000494:Allosteric Regulation; D000818:Animals; D006801:Humans; D008322:Mammals / Q000235:genetics / Q000378:metabolism*; D022022:Nuclear Pore / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism
chemical_list: C424166:KPNB1 protein, human; D028861:Nuclear Pore Complex Proteins; C582177:Nup54 protein, rat; C518579:Nup58 protein, rat; D011994:Recombinant Proteins; D028961:beta Karyopherins