Crossing the Nuclear Envelope: Hierarchical Regulation of Nucleocytoplasmic Transport

Terry, Laura J.; Shows, Eric B.; Wente, Susan R.

doi:10.1126/science.1142204

Cited by 500 publications

(457 citation statements)

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“…It is plausible that translocation between various cellular compartments allows for an added level of spatial regulation of its activity (Kau et al, 2004). The activities of many signaling proteins associated with cancer are regulated by nucleocytoplasmic shuttling (Fabbro and Henderson, 2003;Kau et al, 2004;Terry et al, 2007). It was previously thought that inactive LKB1 is sequestered in the nucleus, whereas it is activated and anchored in the cytoplasm by STRAD␣ where it is biologically active.…”

Section: Discussionmentioning

confidence: 99%

“…The exchange of proteins and RNA between the nucleus and the cytoplasm occurs through the nuclear pore complexes either by passive diffusion (for proteins smaller than ϳ40 KDa) or by active transport, which is facilitated by nuclear transport receptors, also known as karyopherins (Macara, 2001;Suntharalingam and Wente, 2003;Weis, 2003;Terry et al, 2007). There are 26 known mammalian karyopherins, which can be subdivided into three groups, the first of which consists of 10 importins that facilitate the import of proteins into the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Most commonly, shuttling proteins possess both an NLS and a NES. Posttranslational modifications such as phosphorylation and/or binding of cofactors can affect the availability of these signals, allowing for regulation of the nucleocytoplasmic distribution of the shuttling protein (Fabbro and Henderson, 2003;Burack and Shaw, 2005;Terry et al, 2007).Little is known about the molecular mechanisms that allow LKB1 to translocate between the nuclear and the cytoplasmic compartments, or how STRAD␣ and MO25 affect this process. STRAD␣ might induce cytoplasmic accumulation of LKB1 by anchoring it in the cytoplasm and/or inhibiting its import by the classical nuclear import pathway.…”

mentioning

confidence: 99%

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STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

Dorfman

Macara

2008

MBoC

109

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LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRAD␣ and MO25. STRAD␣ induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRAD␣/LKB1 interaction. We investigated the mechanism of nucleocytoplasmic transport of LKB1 in response to its cofactors. Although LKB1 is imported into the nucleus by importin-␣/␤, STRAD␣ and MO25 passively diffuse between the nucleus and the cytoplasm. STRAD␣ induces nucleocytoplasmic shuttling of LKB1. STRAD␣ facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRAD␣ inhibits import of LKB1 by competing with importin-␣ for binding to LKB1. MO25 stabilizes the LKB1-STRAD␣ complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRAD␤, isoform which differs from STRAD␣ in the N-and C-terminal domains that are responsible for interaction with export receptors, does not efficiently relocalize LKB1 from the nucleus to the cytoplasm. These results identify a multifactored mechanism to control LKB1 localization, and they suggest that the STRAD␤-LKB1 complex might possess unique functions in the nucleus. INTRODUCTIONPeutz-Jeghers cancer syndrome is caused by mutations in a gene encoding a serine/threonine kinase called LKB1 (Hemminki et al., 1998). This kinase is closely related to PAR-4, a protein required for polarization of the Caenorhabditis elegans zygote, and it has recently been implicated in the apical/basal polarization of mammalian epithelial cells (Baas et al., 2004). LKB1 is also involved in numerous cell signaling pathways that regulate cellular metabolism (Shaw et al., 2004Liang et al., 2007), cell growth, and responses to DNA damage (Wei et al., 2005;Setogawa et al., 2006;Zeng and Berger, 2006). LKB1 can phosphorylate and activate 13 protein kinases from the AMP-activated protein kinase family (Lizcano et al., 2004). However, the biological significance of this phosphorylation is still unclear for many of these kinases. The cellular localization and activity of LKB1 is controlled through its interaction with Ste20 Related Adaptor (STRAD) and an adapter protein, MO25 . STRAD, a 48-kDa protein, is a pseudokinase that consists of a STE20-like kinase domain but lacks several residues that are indespensible for catalytic activity. STRAD resembles most closely the STE20 homologues SPAK (Johnston et al., 2000) and ILPIP (Sanna et al., 2002), or PAP kinase (Nishigaki et al., 2003). Whereas SPAK is a true kinase, it was later shown that ILPIP/PAPK is a pseudokinase, similarly to STRAD and that it also interacts with and activates LKB1. Therefore, it was termed STRAD␤, whereas the original STRAD became known as STRAD␣ . The complex of LKB1 and STRAD␣ or -␤ is stabilized by MO25, a 40-kDa protein composed of ␣-helical repeats that are distantly related to the armadillo repeat domain (Milburn et al., 2004). MO25 binds STRAD ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

Dorfman

Macara

2008

MBoC

109

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“…Nuclear pore complexes (NPCs) are high molecular weight (50 to 120 MDa from yeast to vertebrates) supramolecular assemblies that confer eukaryotes the ability to transport selectively macromolecules between the nucleus and cytoplasm [61][62][63]. NPCs are highly conserved from yeast to humans, consisting of approximately 30 different nucleoporin proteins that form a central pore of approximately 30 to 60 nm through which small molecules (< 40 kDa) may diffuse freely, but larger molecules may only be transported with the assistance of karyopherin (Kap) receptor proteins [64,65].…”

Section: Nuclear Pore Complexmentioning

confidence: 99%

Conformational dynamics of supramolecular protein assemblies

Kim

Nguyen

Bathe

2011

Journal of Structural Biology

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Supramolecular protein assemblies including molecular motors, cytoskeletal filaments, chaperones, and ribosomes play a central role in a broad array of cellular functions ranging from cell division and motility to RNA and protein synthesis and folding. Single-particle reconstructions of such assemblies have been growing rapidly in recent years, providing increasingly high resolution structural information under native conditions. While the static structure of these assemblies provides essential insight into their mechanism of biological function, their dynamical motions provide additional important information that cannot be inferred from structure alone. Here we present an unsupervised computational framework for the analysis of high molecular weight assemblies and use it to analyze the conformational dynamics of structures deposited in the Electron Microscopy Data Bank. Protein assemblies are modeled using a recently introduced coarse-grained modeling framework based on the finite element method, which is used to compute equilibrium thermal fluctuations, elastic strain energy distributions associated with specific conformational transitions, and dynamical correlations in distant molecular domains. Results are presented in detail for the ribosome-bound termination factor RF2 from Escherichia coli, the nuclear pore complex from Dictyostelium discoideum, and the chaperonin GroEL from E. coli. Elastic strain energy distributions reveal hinge-regions associated with specific conformational change pathways, and correlations in collective molecular motions reveal dynamical coupling between distant molecular domains that suggest new, as well as confirm existing, allosteric mechanisms. Results are publically available for use in further investigation and interpretation of biological function including cooperative transitions, allosteric communication, and molecular mechanics, as well as in further classification and refinement of electron microscopy based structures.

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Nipah virus matrix protein: expert hacker of cellular machines

Watkinson

Lee

2016

FEBS Letters

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Nipah virus (NiV, Henipavirus) is a highly lethal emergent zoonotic paramyxovirus responsible for repeated human outbreaks of encephalitis in South East Asia. There are no approved vaccines or treatments, thus improved understanding of NiV biology is imperative. NiV matrix protein recruits a plethora of cellular machinery to scaffold and coordinate virion budding. Intriguingly, matrix also hijacks cellular trafficking and ubiquitination pathways to facilitate transient nuclear localization. While the biological significance of matrix nuclear localization for an otherwise cytoplasmic virus remains enigmatic, the molecular details have begun to be characterized, and are conserved among matrix proteins from divergent paramyxoviruses. Matrix protein appropriation of cellular machinery will be discussed in terms of its early nuclear targeting and later role in virion assembly.

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Crossing the Nuclear Envelope: Hierarchical Regulation of Nucleocytoplasmic Transport

Cited by 500 publications

References 79 publications

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

Conformational dynamics of supramolecular protein assemblies

Nipah virus matrix protein: expert hacker of cellular machines

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