| Structural highlights
Function
[XPO1_HUMAN] Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap. Several viruses, among them HIV-1, HTLV-1 and influenza A use it to export their unspliced or incompletely spliced RNAs out of the nucleus. Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. Involved in HTLV-1 Rex multimerization.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Chromosome region maintenance 1/exportin1/Xpo1 (CRM1) associates with the GTPase Ran to mediate the nuclear export of proteins bearing a leucine-rich nuclear export signal (NES). CRM1 consists of helical hairpin HEAT repeats and a C-terminal helical extension (C-extension) that inhibits the binding of NES-bearing cargos. We report the crystal structure and small-angle X-ray scattering analysis of a human CRM1 mutant with enhanced NES-binding activity due to deletion of the C-extension. We show that loss of the C-extension leads to a repositioning of CRM1's C-terminal repeats and to a more extended overall conformation. Normal mode analysis predicts reduced rigidity for the deletion mutant, consistent with an observed decrease in thermal stability. Point mutations that destabilize the C-extension shift CRM1 to the more extended conformation, reduce thermal stability, and enhance NES-binding activity. These findings suggest that an important mechanism by which the C-extension regulates CRM1's cargo-binding affinity is by modulating the conformation and flexibility of its HEAT repeats.
Structure of a Truncation Mutant of the Nuclear Export Factor CRM1 Provides Insights into the Auto-Inhibitory Role of Its C-Terminal Helix.,Dian C, Bernaudat F, Langer K, Oliva MF, Fornerod M, Schoehn G, Muller CW, Petosa C Structure. 2013 Jul 9. pii: S0969-2126(13)00202-5. doi:, 10.1016/j.str.2013.06.003. PMID:23850454[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997 Sep 19;90(6):1051-60. PMID:9323133
- ↑ Ossareh-Nazari B, Bachelerie F, Dargemont C. Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science. 1997 Oct 3;278(5335):141-4. PMID:9311922
- ↑ Askjaer P, Jensen TH, Nilsson J, Englmeier L, Kjems J. The specificity of the CRM1-Rev nuclear export signal interaction is mediated by RanGTP. J Biol Chem. 1998 Dec 11;273(50):33414-22. PMID:9837918
- ↑ Hakata Y, Yamada M, Shida H. A multifunctional domain in human CRM1 (exportin 1) mediates RanBP3 binding and multimerization of human T-cell leukemia virus type 1 Rex protein. Mol Cell Biol. 2003 Dec;23(23):8751-61. PMID:14612415
- ↑ Boulon S, Verheggen C, Jady BE, Girard C, Pescia C, Paul C, Ospina JK, Kiss T, Matera AG, Bordonne R, Bertrand E. PHAX and CRM1 are required sequentially to transport U3 snoRNA to nucleoli. Mol Cell. 2004 Dec 3;16(5):777-87. PMID:15574332 doi:10.1016/j.molcel.2004.11.013
- ↑ Fei E, Ma X, Zhu C, Xue T, Yan J, Xu Y, Zhou J, Wang G. Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression. J Biol Chem. 2010 Dec 3;285(49):38630-40. doi: 10.1074/jbc.M110.107912. Epub 2010, Oct 4. PMID:20921223 doi:10.1074/jbc.M110.107912
- ↑ Dian C, Bernaudat F, Langer K, Oliva MF, Fornerod M, Schoehn G, Muller CW, Petosa C. Structure of a Truncation Mutant of the Nuclear Export Factor CRM1 Provides Insights into the Auto-Inhibitory Role of Its C-Terminal Helix. Structure. 2013 Jul 9. pii: S0969-2126(13)00202-5. doi:, 10.1016/j.str.2013.06.003. PMID:23850454 doi:10.1016/j.str.2013.06.003
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