Atomic basis of CRM1-cargo recognition, release and inhibition

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 and quite a few of its cargos are misregulated in the diseases and hence 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 the structure-function studies that explain CRM1-cargo recognition, release and inhibition.

Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

“…5 Exportin 1 (XPO1), also called chromosome region maintenance protein 1 (CRM1), is a critical mediator of nuclear export responsible for shuttling more than 200 known cargo proteins from the nucleus to the cytoplasm, including TSPs and anti-inflammatory and growthregulating proteins. 6,7 XPO1 overexpression has been reported in several hematologic and solid malignancies and is correlated with poor patient outcomes. [7][8][9][10][11][12] XPO1 overexpression is one mechanism by which neoplastic cells inactivate TSPs through nuclear exclusion and thereby circumvent cell-cycle regulation, genome survey, and apoptosis.…”

“…9 Selinexor is a novel, orally bioavailable small molecule, which inhibits XPO1 by covalently and reversibly binding cysteine-528, an essential residue for XPO1 cargo binding. 6 Inhibition of XPO1 results in nuclear accumulation of p53, pRb, p21, p27, BRCA1/2, FOXOs, survivin, and other proteins. 6,7 Accumulation of TSPs in the nucleus restores cell-cycle checkpoints and induces growth arrest and apoptosis in malignant cells.…”

“…6 Inhibition of XPO1 results in nuclear accumulation of p53, pRb, p21, p27, BRCA1/2, FOXOs, survivin, and other proteins. 6,7 Accumulation of TSPs in the nucleus restores cell-cycle checkpoints and induces growth arrest and apoptosis in malignant cells. 13,14 Preclinical studies in a wide range of sarcoma cell lines and xenografts have demonstrated robust antitumor activity.…”

Balancing the yin and yang of SINE

“…2 chromosome region maintenance 1 (CRM1), exportin 1, or XPO1, is uniquely required for the export of .200 different proteins to the cytoplasm, including nucleophosmin, survivin, p27, APC, BRCA1, and p53. 3 The effects of shuttled proteins often depend on their location; for example, in the nucleus, survivin helps attach centromeres to mitotic spindles, whereas in the cytoplasm, it interacts with caspases to inhibit apoptosis. 4 These proteins are prominent targets of oncogenic mutations, as are the components of the nuclear transport system that modulate their effects.…”

Give me a SINE: how Selective Inhibitors of Nuclear Export modulate autophagy and aging

“…This dynamic process is driven by the interaction between karyopherins and cargoes, which are powered by ras-related nuclear protein-GTPases (RanGTPases) for transport across the nuclear pore (Reviewed in 1 ). Importins mediate the import of proteins with nuclear localization sequences while exportins facilitate the nuclear export of proteins containing nuclear export sequences.…”