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The adapter importin-alpha provides flexible control of nuclear import at the expense of efficiency.

Riddick G, Macara IG - Mol. Syst. Biol. (2007)

Bottom Line: However, computer simulations predicted the opposite outcome, and showed that direct transport is faster than adapter-mediated transport.These predictions were validated experimentally.The data, together with previous analyses of nuclear protein import, suggest that the use of adapters such as importin-alpha provides the cell with increased dynamic range for control of nuclear import rates, but at the expense of efficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Virginia, Charlottesville, VA 22908, USA.

ABSTRACT
Although there exists a large family of nuclear transport receptors (Karyopherins), the majority of known import cargoes use an adapter protein, Importin-alpha (Impalpha), which links the cargo to a karyopherin, Importin-beta (Impbeta). The reason for the existence of transport adapters is unknown. One hypothesis is that, as Impalpha re-export is coupled to GTP hydrolysis, it can drive a higher concentration of nuclear cargo than could be achieved by direct cargo binding to Importin-beta. However, computer simulations predicted the opposite outcome, and showed that direct transport is faster than adapter-mediated transport. These predictions were validated experimentally. The data, together with previous analyses of nuclear protein import, suggest that the use of adapters such as importin-alpha provides the cell with increased dynamic range for control of nuclear import rates, but at the expense of efficiency.

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Overview of the CRM1/RanBP3 export model. (A) The entire nuclear transport model includes modules for cargo import, Karyopherin transport, Ran transport, cargo export, and the NPC. (B) Detail of the cargo export module. RanBP3, CRM1, RanGTP, and the NES cargo combine to form an export complex. After translocating through the NPC, RanBP1 binds to the complex and allows RanGAP to hydrolyze RanGTP to RanGDP, releasing the cargo and disassociating the complex. RanBP3 contains an NLS and is imported into the nucleus by Impα/Impβ. (C) Detail of the Nuclear Pore Complex module. The NPC is represented as a single separate compartment containing nucleoporins that bind the cargo complex.
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f1: Overview of the CRM1/RanBP3 export model. (A) The entire nuclear transport model includes modules for cargo import, Karyopherin transport, Ran transport, cargo export, and the NPC. (B) Detail of the cargo export module. RanBP3, CRM1, RanGTP, and the NES cargo combine to form an export complex. After translocating through the NPC, RanBP1 binds to the complex and allows RanGAP to hydrolyze RanGTP to RanGDP, releasing the cargo and disassociating the complex. RanBP3 contains an NLS and is imported into the nucleus by Impα/Impβ. (C) Detail of the Nuclear Pore Complex module. The NPC is represented as a single separate compartment containing nucleoporins that bind the cargo complex.

Mentions: To investigate cargo gradients in both types of import, we developed a 3-compartment in silico transport model (Figure 1). Details of the model are in Materials and methods, and the complete schematic for the cargo import, Ran transport, and Karyopherin transport modules can be found in the Supplementary Data by Riddick and Macara (2005). Addition of either type of cargo to the cytoplasm was simulated by instantaneously stepping its concentration from 0 to 4 μM and measuring nuclear accumulation over 1800 s. Unexpectedly, cargo imported directly by Impβ had a greater initial rate and a higher steady-state nuclear accumulation than cargo imported via the adapter, Impα (Figure 2A). This difference results from the greater reaction rate for a bimolecular interaction, faster cycling time of Impβ between the nucleus and the cytoplasm, and the slightly higher permeability for the Impβ–cargo complex through the NPC, as compared to the Impα/β–cargo complex.


The adapter importin-alpha provides flexible control of nuclear import at the expense of efficiency.

Riddick G, Macara IG - Mol. Syst. Biol. (2007)

Overview of the CRM1/RanBP3 export model. (A) The entire nuclear transport model includes modules for cargo import, Karyopherin transport, Ran transport, cargo export, and the NPC. (B) Detail of the cargo export module. RanBP3, CRM1, RanGTP, and the NES cargo combine to form an export complex. After translocating through the NPC, RanBP1 binds to the complex and allows RanGAP to hydrolyze RanGTP to RanGDP, releasing the cargo and disassociating the complex. RanBP3 contains an NLS and is imported into the nucleus by Impα/Impβ. (C) Detail of the Nuclear Pore Complex module. The NPC is represented as a single separate compartment containing nucleoporins that bind the cargo complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1911202&req=5

f1: Overview of the CRM1/RanBP3 export model. (A) The entire nuclear transport model includes modules for cargo import, Karyopherin transport, Ran transport, cargo export, and the NPC. (B) Detail of the cargo export module. RanBP3, CRM1, RanGTP, and the NES cargo combine to form an export complex. After translocating through the NPC, RanBP1 binds to the complex and allows RanGAP to hydrolyze RanGTP to RanGDP, releasing the cargo and disassociating the complex. RanBP3 contains an NLS and is imported into the nucleus by Impα/Impβ. (C) Detail of the Nuclear Pore Complex module. The NPC is represented as a single separate compartment containing nucleoporins that bind the cargo complex.
Mentions: To investigate cargo gradients in both types of import, we developed a 3-compartment in silico transport model (Figure 1). Details of the model are in Materials and methods, and the complete schematic for the cargo import, Ran transport, and Karyopherin transport modules can be found in the Supplementary Data by Riddick and Macara (2005). Addition of either type of cargo to the cytoplasm was simulated by instantaneously stepping its concentration from 0 to 4 μM and measuring nuclear accumulation over 1800 s. Unexpectedly, cargo imported directly by Impβ had a greater initial rate and a higher steady-state nuclear accumulation than cargo imported via the adapter, Impα (Figure 2A). This difference results from the greater reaction rate for a bimolecular interaction, faster cycling time of Impβ between the nucleus and the cytoplasm, and the slightly higher permeability for the Impβ–cargo complex through the NPC, as compared to the Impα/β–cargo complex.

Bottom Line: However, computer simulations predicted the opposite outcome, and showed that direct transport is faster than adapter-mediated transport.These predictions were validated experimentally.The data, together with previous analyses of nuclear protein import, suggest that the use of adapters such as importin-alpha provides the cell with increased dynamic range for control of nuclear import rates, but at the expense of efficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Virginia, Charlottesville, VA 22908, USA.

ABSTRACT
Although there exists a large family of nuclear transport receptors (Karyopherins), the majority of known import cargoes use an adapter protein, Importin-alpha (Impalpha), which links the cargo to a karyopherin, Importin-beta (Impbeta). The reason for the existence of transport adapters is unknown. One hypothesis is that, as Impalpha re-export is coupled to GTP hydrolysis, it can drive a higher concentration of nuclear cargo than could be achieved by direct cargo binding to Importin-beta. However, computer simulations predicted the opposite outcome, and showed that direct transport is faster than adapter-mediated transport. These predictions were validated experimentally. The data, together with previous analyses of nuclear protein import, suggest that the use of adapters such as importin-alpha provides the cell with increased dynamic range for control of nuclear import rates, but at the expense of efficiency.

Show MeSH