Abstract
Ran-binding protein 3 (RanBP3) is an approximately 55-kDa protein that functions as a cofactor for Crm1-mediated nuclear export. RanBP3 stimulates export by enhancing the affinity of Crm1 for Ran.GTP and cargo. However, important additional functions for this cofactor may exist. We now report that RanBP3 associates with the Ran-specific guanine nucleotide exchange factor, regulator of chromosome condensation 1 (RCC1). This interaction was stimulated by the addition of Ran; moreover, Ran.GDP, Ran.GTP, and Ran without nucleotide could all stimulate complex formation between RanBP3 and RCC1 even though binding of Ran.GDP to RanBP3 alone was undetectable. RanBP3 could also promote binding of Crm1 to RCC1 in the presence of Ran. Binding of RanBP3 to RCC1 increased the catalytic activity of RCC1 toward Ran, and importantly, the ability of RanBP3 to stimulate RCC1 was not affected by the presence of Crm1. These data indicate that RanBP3 acts as a scaffold protein to promote the efficient assembly of export complexes. By tethering Crm1 to catalytically enhanced RCC1, RanBP3 may lower the entropic barrier for the loading of Ran.GTP onto Crm1. We propose that this provides an additional mechanism by which RanBP3 facilitates export.
Highlights
From the Departments of ‡Microbiology and §Pharmacology, The Center for Cell Signaling, The University of Virginia, Charlottesville, Virginia 22908
We report that Ran-binding protein 3 (RanBP3) associates with the Ran-specific guanine nucleotide exchange factor, regulator of chromosome condensation 1 (RCC1)
All nuclear transport is believed to occur through the nuclear pore complex (NPC),1 a large glycoprotein complex that spans the double membrane of the nuclear envelope [3]
Summary
A single guanine nucleotide exchange factor (RCC1) and GTPase-activating protein (RanGAP) catalyze the Ran GDP/GTP cycle [4, 5] The Crm1-cargo-Ran1⁄7GTP complex translocates across the NPC and is dissociated by hydrolysis of GTP on Ran, stimulated by RanGAP and other required factors. Nxt binds directly to Crm and Ran and facilitates the delivery of the export complex to the cytoplasmic face of the NPC [13] Another protein, eukaryotic initiation factor-5A, may enhance the affinity of Crm for the NES of the human immunodeficiency virus, type 1 protein Rev [14]. The quaternary Crm1-RanBP3-Ran1⁄7GTP-NES complex is able to interact with the NPC, mediating transport from the nucleus to the cytoplasm. We propose that RanBP3 acts as a scaffold protein to promote the efficient assembly of Crm1-dependent export complexes
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