Atomic basis of CRM1-cargo recognition, release and inhibition - PubMed (original) (raw)
Review
Atomic basis of CRM1-cargo recognition, release and inhibition
Ho Yee Joyce Fung et al. Semin Cancer Biol. 2014 Aug.
Abstract
CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as the transport receptor is overexpressed in many cancers where some of its cargos are misregulated and mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes structure-function studies that explain CRM1-cargo recognition, release and inhibition.
Keywords: Exportin; Karyopherin; NES; Nuclear export; Nuclear pore complex.
Published by Elsevier Ltd.
Conflict of interest statement
Conflict of Interest
YMC, consultancy, Karyopharm Therapeutics Inc.
Figures
Figure 1. Schematic of the CRM1 nuclear export cycle
In the nucleus, RanGTP is efficiently loaded with GTP by RCC1. RanGTP and cargo forms a complex with CRM1 and is exported through the nuclear pore complex to the cytoplasm. RanGAP1 and RanBP1 facilitate cargo release and RanGTP hydrolysis. CRM1 is then recycled back to the nucleus for another round of export.
Figure 2. Architecture of full-length CRM1
A) Crystal structures of the human CRM1-SNUPN complex (PDB ID: 3GB8) and B) the mouse CRM1-RanGTP-SNUPN complex (3GJX). The 21 HEAT repeats of CRM1 are in yellow with individual helices drawn as cylinders. The two key switch features of CRM1, the H9 Loop and the C-terminal extension (helix H21B and C-terminal tail), are in magenta and green respectively. H11 and H12 that make up the NES binding groove are labelled. SNUPN (cyan) and RanGTP (pink) are shown as surface representations.
Figure 3. Cargo-bound CRM1 complexes
A) Structures of the same human CRM1-SNUPN and B) mouse CRM1-RanGTP-SNUPN complexes in Fig 2, but shown here with more details to explain CRM1-cargo recognition. Surface representations of the NES binding groove of the mouse CRM1-RanGTP-SNUPN complex, C) with the SNUPN NES bound, D) the NES peptide removed to view the underlying Φ0-4 pockets in the groove, E) the PKI NES bound (3NBY) and F) the HIV-1 Rev-NES bound (3NBZ). NES peptides are shown in cartoon with their side chains in sticks. The three peptides have diverse amino acid sequences and adopt different secondary structures to accommodate their hydrophobic side chains into the same Φ0-4 hydrophobic pockets.
Figure 4. Unliganded CRM1
A) Unliganded S. cerevisiae CRM1 (3VYC), B) unliganded C. thermophilum CRM1 (4FGV) and C) the unliganded C-terminally truncated mutant of human CRM1 (4BSM). All three unliganded CRM1 proteins have similar conformations with their H9 loops associating with H11-H12 at the back of the NES groove. H11 and H12 that make up the NES binding groove are labelled. The H9 loops and C-terminal extensions are in magenta and green, respectively. D) The closed NES binding groove in unliganded S. cerevisiae CRM1 is shown as surface representation with underlying helices and side chains shown as cartoons and sticks.
Figure 5. The CRM1-RanGTP-RanBP1 complex
Structure of the CRM1-RanGTP-RanBP1 complex (3M1I). A) CRM1 is yellow with its H9 loop in magenta and C-terminal extension in green. RanGTP is in cyan with GTP in sticks, and RanBP1 is orange. B) Same as A, but RanBP1 is removed to better view the C-terminal tail of RanGTP and the H9 loop of CRM1. Interactions of RanBP1 with the C-terminal tail of RanGTP and positioning of the latter results in steric clash of the Ran tail with the CRM1 H9 loop of CRM1 in its active configuration at H15-H16 (as seen in Fig. 3B) and stabilization of the inactive conformation of the H9 loop at H11-H12. Relevant HEAT repeats 11, 12, 15 and 16 are labelled.
Figure 6. CRM1 bound to small molecule inhibitors
A) Chemical structures of Leptomycin B (LMB), KPT-185 and KPT-251. B) Chemical reactions showing conjugation of LMB to the groove cysteine residue of CRM1 and the subsequent hydrolysis. Positions of α-protons of the Michael reaction sites are denoted by asterisks. The CRM1 NES groove bound to C) LMB (4HAT), D) KPT-185 (4GMX) E) KPT-251 (4GPT). The reactive cysteine residue in the CRM1 NES groove which these inhibitors conjugate to is labelled.
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