A Long Disordered Linker in Nuclear Transport of Membrane Proteins

Abstract

Nuclear Pore Complexes (NPCs) embedded in the nuclear envelope allow selective transport of macromolecules between the cytosol and nucleoplasm. Transport factors shuttle cargo though the NPCs by interacting with the disordered proteins that encode the binding sites for the transport factors, the FG-repeat domains. Also the traffic of integral membrane proteins between the outer and inner membranes of the nuclear envelope occurs via the NPCs. Two baker's yeast proteins, Heh2 and Heh1 (Src1), rely on the transport factor Kap60 and FG-repeat-proteins for their transport through the NPC1(1,2). Heh1 and Heh2 feature a high affinity binding site for Kap60, that is spaced from the transmembrane domain by a 180 or 235 amino acid long intrinsically disordered linker. A clear relationship between linker length and transport to the inner membrane was observed while randomizing the amino acid sequence of the linker had no effect. We proposed that during transport the disordered linker enables the interactions between the transport factor and FG-Nups by dodging into the NPC, and extending the transport factor away from the membrane. Ongoing work is aimed at testing the proposed transport mechanism, and includes studying the relationship between the compositions of the disordered linker regions, stokes radius, and transport. 1: King MC, Lusk CP, Blobel G. Nature. 2006 442(7106):1003-7. 2: Meinema AC, Laba JK, Hapsari RA, Otten R, Mulder FA, Kralt A, van den Bogaart G, Lusk CP, Poolman B, Veenhoff LM. Science. 2011 333(6038):90-3.