Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

654 Chapter 12: Intracellular Compartments and Protein Sorting
protein with nuclear
localization signal (cargo)
nuclear import
receptor
nuclear export
receptor
cargo delivered to cytosol
Ran-GDP DISSOCIATES
FROM RECEPTORS
cytosolic
fibril
+
P i
Ran-GDP
+
P i
Ran-GDP
CYTOSOL
NUCLEUS
Ran-GTP
Ran-GTP
cargo delivered
to nucleus
Ran-GTP BINDS TO
RECEPTORS
protein with nuclear
export signal (cargo)
(A) NUCLEAR IMPORT
(B) NUCLEAR EXPORT
This gradient of the two conformational forms of Ran drives nuclear transport
in the appropriate direction. Docking of nuclear import receptors to FG-repeats
on the cytosolic side of the NPC, for example, occurs MBoC6 whether m12.15/12.14 or not these receptors
are loaded with appropriate cargo. Import receptors, facilitated by FG-repeat
binding, then enter the channel. If they reach the nuclear side of the pore complex,
Ran-GTP binds to them, and, if the receptors arrive loaded with cargo molecules,
the Ran-GTP binding causes the receptors to release their cargo (Figure
12–13A). Because the Ran-GDP in the cytosol does not bind to import (or export)
receptors, unloading occurs only on the nuclear side of the NPC. In this way, the
nuclear localization of Ran-GTP creates the directionality of the import process.
Having discharged its cargo in the nucleus, the empty import receptor with
Ran-GTP bound is transported back through the pore complex to the cytosol.
There, Ran-GAP triggers Ran-GTP to hydrolyze its bound GTP, thereby converting
it to Ran-GDP, which dissociates from the receptor. The receptor is then ready for
another cycle of nuclear import.
Nuclear export occurs by a similar mechanism, except that Ran-GTP in the
nucleus promotes cargo binding to the export receptor, rather than promoting
cargo dissociation. Once the export receptor moves through the pore to the cytosol,
it encounters Ran-GAP, which induces the receptor to hydrolyze its GTP to
GDP. As a result, the export receptor releases both its cargo and Ran-GDP in the
cytosol. Free export receptors are then returned to the nucleus to complete the
cycle (Figure 12–13B).
Figure 12–13 How GTP hydrolysis
by Ran in the cytosol provides
directionality to nuclear transport.
Movement through the NPC of loaded
nuclear transport receptors occurs along
the FG-repeats displayed by certain NPC
proteins. The differential localization of
Ran-GTP in the nucleus and Ran-GDP
in the cytosol provides directionality (red
arrows) to both nuclear import (A) and
nuclear export (B). Ran-GAP stimulates the
hydrolysis of GTP to produce Ran-GDP on
the cytosolic side of the NPC (see Figure
12–12).
Transport Through NPCs Can Be Regulated by Controlling Access
to the Transport Machinery
Some proteins contain both nuclear localization signals and nuclear export signals.
These proteins continually shuttle back and forth between the nucleus and
the cytosol. The relative rates of their import and export determine the steadystate
localization of such shuttling proteins: if the rate of import exceeds the rate
of export, a protein will be located mainly in the nucleus; conversely, if the rate of
export exceeds the rate of import, a protein will be located mainly in the cytosol.
Thus, changing the rate of import, export, or both, can change the location of a
protein.