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

656 Chapter 12: Intracellular Compartments and Protein Sorting
(A)
HIGH CHOLESTEROL
SCAP
cholesterol
ER
CYTOSOL
SREBP
(B)
ER
LOW CHOLESTEROL
During Mitosis the Nuclear Envelope Disassembles
GOLGI
site 2
protease
released factor
cholesterol biosynthesis enzymes
site 1 protease
NUCLEUS
The nuclear lamina, located on the nuclear side of the inner nuclear membrane,
is a meshwork of interconnected protein subunits called nuclear lamins. The
lamins are a special class of intermediate filament proteins (discussed in Chapter
16) that polymerize into a two-dimensional lattice (Figure 12–17). The nuclear
lamina gives shape and stability to the nuclear envelope, to which it is anchored
by attachment to both the NPCs and transmembrane proteins of the inner nuclear
membrane. The lamina also interacts directly with chromatin, which itself interacts
with transmembrane proteins of the inner nuclear membrane. Together with
the lamina, these inner membrane MBoC6 n12.702/12.18
proteins provide structural links between the
DNA and the nuclear envelope.
When a nucleus is dismantled during mitosis, the NPCs and nuclear lamina
disassemble and the nuclear envelope fragments. The dismantling process is at
least partly a consequence of direct phosphorylation of nucleoporins and lamins
by the cyclin-dependent protein kinase (Cdk) that is activated at the onset of mitosis
(discussed in Chapter 17). During this process, some NPC proteins become
bound to nuclear import receptors, which play an important part in the reassembly
of NPCs at the end of mitosis. Nuclear envelope membrane proteins—no longer
tethered to the pore complexes, lamina, or chromatin—disperse throughout
the ER membrane. The dynein motor protein, which moves along microtubules
(discussed in Chapter 16), actively participates in tearing the nuclear envelope off
the chromatin. Together, these processes break down the barriers that normally
separate the nucleus and cytosol, and the nuclear proteins that are not bound to
membranes or chromosomes intermix completely with the proteins of the cytosol
(Figure 12–18).
Later in mitosis, the nuclear envelope reassembles on the surface of the
daughter chromosomes. In addition to its crucial role in nuclear transport, the
Ran GTPase also acts as a positional marker for chromatin during cell division,
when the nuclear and cytosolic components intermix. Because Ran-GEF remains
bound to chromatin when the nuclear envelope breaks down, Ran molecules
close to chromatin are mainly in their GTP-bound conformation. By contrast, Ran
molecules further away have a high likelihood of encountering Ran-GAP, which
is distributed throughout the cytosol; these Ran molecules are mainly in their
GDP-bound conformation. As a result, the chromosomes in mitotic cells are surrounded
by a cloud of Ran-GTP. Ran-GTP releases the NPC proteins in proximity
to the chromosomes from nuclear import receptors. The free NPC proteins attach
Figure 12–16 Feedback regulation
of cholesterol biosynthesis. SREBP
(sterol response element binding protein),
a latent transcription regulator that controls
expression of cholesterol biosynthetic
enzymes, is initially synthesized as an ER
membrane protein. It is anchored in the
ER if there is sufficient cholesterol in the
membrane by interaction with another
ER membrane protein, called SCAP
(SREBP cleavage activation protein),
which binds cholesterol. If the cholesterol
binding site on SCAP is empty (at low
cholesterol concentrations), SCAP changes
conformation and is packaged together
with SREBP into transport vesicles, which
deliver their cargo to the Golgi apparatus,
where two Golgi-resident proteases cleave
SREBP to free its cytosolic domain from
the membrane. The cytosolic domain then
moves into the nucleus, where it binds
to the promoters of genes that encode
proteins involved in cholesterol biosynthesis
and activates their transcription. In this
way, more cholesterol is made when its
concentration falls below a threshold.
1 µm
Figure 12–17 The nuclear lamina. An
electron micrograph of a portion of the
nuclear lamina in a Xenopus oocyte prepared
by freeze-drying and metal shadowing.
The lamina is formed by a regular lattice of
specialized intermediate filaments. Lamins
are only present in metazoan cells. Other,
yet-unknown proteins may serve similar
functions in species that lack lamins.
(Courtesy of Ueli Aebi.)
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