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

THE TRANSPORT OF MOLECULES BETWEEN THE NUCLEUS AND THE CYTOSOL
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cargo
protein 1
nuclear import
receptor
(A)
cargo
protein 2
cargo
protein 3
nuclear localization signals
nuclear import
adaptor protein
cargo
protein 4
nuclear
import
receptor
(B)
system. The transport system relies on nuclear export signals on the macromolecules
to be exported, as well as on complementary nuclear export receptors,
or exportins. These receptors bind to both the export signal and NPC proteins to
guide their cargo through the NPC to the cytosol.
Many nuclear export receptors are structurally related to nuclear import
receptors, and they are encoded MBoC6 by the 12.13/12.13 same gene family of nuclear transport
receptors, or karyopherins. In yeast, there are 14 genes encoding karyopherins; in
animal cells, the number is significantly larger. It is often not possible to tell from
their amino acid sequence alone whether a particular family member works as a
nuclear import or nuclear export receptor. As might be expected, therefore, the
import and export transport systems work in similar ways but in opposite directions:
the import receptors bind their cargo molecules in the cytosol, release them
in the nucleus, and are then exported to the cytosol for reuse, while the export
receptors function in the opposite fashion.
The Ran GTPase Imposes Directionality on Transport Through
NPCs
The import of nuclear proteins through NPCs concentrates specific proteins in the
nucleus and thereby increases order in the cell. The cell fuels this ordering process
by harnessing energy stored in concentration gradients of the GTP-bound form
of the monomeric GTPase Ran, which is required for both nuclear import and
export.
Like other GTPases, Ran is a molecular switch that can exist in two conformational
states, depending on whether GDP or GTP is bound (discussed in Chapter
3). Two Ran-specific regulatory proteins trigger the conversion between the two
states: a cytosolic GTPase-activating protein (GAP) triggers GTP hydrolysis and
thus converts Ran-GTP to Ran-GDP, and a nuclear guanine exchange factor (GEF)
promotes the exchange of GDP for GTP and thus converts Ran-GDP to Ran-GTP.
Because Ran-GAP is located in the cytosol and Ran-GEF is located in the nucleus
where it is anchored to chromatin, the cytosol contains mainly Ran-GDP, and the
nucleus contains mainly Ran-GTP (Figure 12–12).
Ran-GAP
P i
Ran-GTP
Ran-GDP
GDP
GTP
GDP
GTP
CYTOSOL
NUCLEUS
Ran-GEF
chromatin
Figure 12–11 Nuclear import receptors
(importins). (A) Different nuclear import
receptors bind different nuclear localization
signals and thereby different cargo
proteins. (B) Cargo protein 4 requires an
adaptor protein to bind to its nuclear import
receptor. The adaptors are structurally
related to nuclear import receptors and
recognize nuclear localization signals
on cargo proteins. They also contain a
nuclear localization signal that binds them
to an import receptor, but this signal only
becomes exposed when they are loaded
with a cargo protein.
Figure 12–12 The compartmentalization
of Ran-GDP and Ran-GTP. Localization
of Ran-GDP in the cytosol and Ran-GTP in
the nucleus results from the localization of
two Ran regulatory proteins: Ran GTPaseactivating
protein (Ran-GAP) is located in
the cytosol, and Ran guanine nucleotide
exchange factor (Ran-GEF) binds to
chromatin and is therefore located in the
nucleus.
Ran-GDP is imported into the nucleus by
its own import receptor, which is specific
for the GDP-bound conformation of Ran.
The Ran-GDP receptor is structurally
unrelated to the main family of nuclear
transport receptors. However, it also
binds to FG-repeats in NPC channel
nucleoporins.