Non-transport roles of nuclear import receptors: In need of the right balance (original) (raw)
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Importin-beta-like nuclear transport receptors
Genome biology, 2001
In recent years, our understanding of macromolecular transport processes across the nuclear envelope has grown dramatically, and a large number of soluble transport receptors mediating either nuclear import or nuclear export have been identified. Most of these receptors belong to one large family of proteins, all of which share homology with the protein import receptor importin beta (also named karyopherin beta). Members of this family have been classified as importins or exportins on the basis of the direction they carry their cargo. To date, the family includes 14 members in the yeast Saccharomyces cerevisiae and at least 22 members in humans. Importins and exportins are regulated by the small GTPase Ran, which is thought to be highly enriched in the nucleus in its GTP-bound form. Importins recognize their substrates in the cytoplasm and transport them through nuclear pores into the nucleus. In the nucleoplasm, RanGTP binds to importins, inducing the release of import cargoes. In ...
Importin α: a multipurpose nuclear-transport receptor
Trends in Cell Biology, 2004
The importin a/b heterodimer targets hundreds of proteins to the nuclear-pore complex (NPC) and facilitates their translocation across the nuclear envelope. Importin a binds to classical nuclear localization signal (cNLS)-containing proteins and links them to importin b, the karyopherin that ferries the ternary complex through the NPC. A second karyopherin, the exportin CAS, recycles importin a back to the cytoplasm. In this article, we discuss control mechanisms that importin a exerts over the assembly and disassembly of the ternary complex and we describe how new groups of importin a genes arose during the evolution of metazoan animals to function in development and differentiation. We also describe activities of importin a that seem to be distinct from its housekeeping functions in nuclear transport.
Dynamic localization of the nuclear import receptor and its interactions with transport factors
The Journal of Cell Biology, 1996
Characterization of the interactions between soluble factors required for nuclear transport is key to understanding the process of nuclear trafficking. Using a synthetic lethal screen with the rnal-1 strain, we have identified a genetic interaction between Rnalp, a GTPase activating protein required for nuclear transport, and yeast importin-[3, a component of the nuclear localization signal receptor. By the use of fusion proteins, we demonstrate that Rnalp physically interacts with importin-~. Mutants in importin-~ exhibit in vivo nuclear protein import defects, and importin-[3 localizes to the nuclear envelope along with other proteins associated with the nuclear pore complex. In addition, we present evidence that importin-ot, but not importin-13, mislocalizes to the nucleus in cells where the GTPase Ran is likely to be in the GDP-bound state. We suggest a model of nuclear transport in which Ran-mediated hydrolysis of GTP is necessary for the import of importin-a and the nuclear localization signal-bearing substrate into the nucleus, while exchange of GDP for GTP on Ran is required for the export of both mRNA and importin-a from the nucleus.
Stimulated nuclear import by β-like importins
F1000Prime Reports, 2013
Classic nuclear shuttling is mediated by an importin-a • b heterodimer that binds to cargoes containing a nuclear localization signal, and shuttles most nuclear proteins immediately after their translation. Aside from this canonical mechanism, kariopheryn-bs or b-like importins operate by binding to non-canonical nuclear localization signals to mediate translocation without the assistance of importin-a. The mechanism by which these components operate is much less understood and is currently under investigation. Recently, several b-like importins have been implicated in the stimulated nuclear translocation of signaling proteins. Here, we propose that this group of importins might be responsible for the swift nuclear shuttling of many proteins following various stimuli.
Structural biology and regulation of protein import into the nucleus
Journal of molecular biology, 2015
Proteins are translated in the cytoplasm, but many need to access the nucleus to perform their functions. Understanding how these nuclear proteins are transported through the nuclear envelope and how the import processes are regulated is therefore an important aspect of understanding cell function. Structural biology has played a key role in understanding the molecular events during the transport processes and their regulation, including the recognition of nuclear targeting signals by the corresponding receptors. Here, we review the structural basis of the principal nuclear import pathways and the molecular basis of their regulation. The pathways involve transport factors that are members of the β-karyopherin family, which can bind cargo directly (e.g. importin-β, transportin-1, transportin-3, importin-13) or through adaptor proteins (e.g. importin-α, snurportin-1, symportin-1), as well as unrelated transport factors such as Hikeshi, involved in the transport of heat-shock proteins,...
Importin-mediated nuclear transport in neurons
Current Opinion in Neurobiology, 2006
The polarized morphology of neurons poses a particular challenge to intracellular signal transduction. Local signals generated at distal sites must be retrogradely transported to the nucleus to produce persistent changes in neuronal function. Such communication of signals between distal neuronal compartments and the nucleus occurs during axon guidance, synapse formation, synaptic plasticity and following neuronal injury. Recent studies have begun to delineate a role for the active nuclear import pathway in transporting signals from axons and dendrites to the nucleus. In this pathway, soluble cargo proteins are recognized by nuclear transport carriers, called importins, which mediate their translocation from the cytoplasm into the nucleus. In neurons, importins might serve an additional function by carrying signals from distal sites to the soma.
Molecular and Cellular Biology, 2006
The "classical" nuclear protein import pathway depends on importin alpha and importin beta. Importin alpha binds nuclear localization signal (NLS)-bearing proteins and functions as an adapter to access the importin beta-dependent import pathway. In humans, only one importin beta is known to interact with importin alpha, while six alpha importins have been described. Various experimental approaches provided evidence that several substrates are transported specifically by particular alpha importins. Whether the NLS is sufficient to mediate importin alpha specificity is unclear. To address this question, we exchanged the NLSs of two well-characterized import substrates, the seven-bladed propeller protein RCC1, preferentially transported into the nucleus by importin alpha3, and the less specifically imported substrate nucleoplasmin. In vitro binding studies and nuclear import assays revealed that both NLS and protein context contribute to the specificity of importin alpha binding and transport.
The Journal of Cell Biology, 2005
14-3-3 proteins are phosphoserine/threonine-binding proteins that play important roles in many regulatory processes, including intracellular protein targeting. 14-3-3 proteins can anchor target proteins in the cytoplasm and in the nucleus or can mediate their nuclear export. So far, no role for 14-3-3 in mediating nuclear import has been described. There is also mounting evidence that nuclear import is regulated by the phosphorylation of cargo proteins, but the underlying mechanism remains elusive. Myopodin is a dual-compartment, actin-bundling protein that functions as a tumor suppressor in human bladder cancer. In muscle cells, myopodin redistributes between the nucleus and the cytoplasm in a differentiation-dependent and stress-induced fashion. We show that importin α binding and the subsequent nuclear import of myopodin are regulated by the serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. These results establish a novel paradigm for the promotion of nucl...