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J. Cell Biol.,
Volume 140, Number 3, February 9, 1998 499-509
Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York 10021
RanGAP1 is the GTPase-activating protein
for Ran, a small ras-like GTPase involved in regulating
nucleocytoplasmic transport. In vertebrates, RanGAP1
is present in two forms: one that is cytoplasmic, and another that is concentrated at the cytoplasmic fibers of nuclear pore complexes (NPCs). The NPC-associated
form of RanGAP1 is covalently modified by the small
ubiquitin-like protein, SUMO-1, and we have recently
proposed that SUMO-1 modification functions to target RanGAP1 to the NPC. Here, we identify the domain of RanGAP1 that specifies SUMO-1 modification
and demonstrate that mutations in this domain that inhibit modification also inhibit targeting to the NPC.
Targeting of a heterologous protein to the NPC depended on determinants specifying SUMO-1 modification and also on additional determinants in the COOH-terminal domain of RanGAP1. SUMO-1 modification
and these additional determinants were found to specify interaction between the COOH-terminal domain of
RanGAP1 and a region of the nucleoporin, Nup358,
between Ran-binding domains three and four. Together, these findings indicate that SUMO-1 modification targets RanGAP1 to the NPC by exposing, or creating, a Nup358 binding site in the COOH-terminal
domain of RanGAP1. Surprisingly, the COOH-terminal domain of RanGAP1 was also found to harbor a
nuclear localization signal. This nuclear localization signal, and the presence of nine leucine-rich nuclear export signal motifs, suggests that RanGAP1 may shuttle
between the nucleus and the cytoplasm.
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