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 ENDOPLASMIC RETICULUM
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As discussed in Chapter 13, the plasma membrane and the membranes of the
Golgi apparatus, lysosomes, and endosomes all form part of a membrane system
that communicates with the ER by means of transport vesicles, which transfer
both proteins and lipids. Mitochondria and plastids, however, do not belong to
this system, and they therefore require different mechanisms to import proteins
and lipids for growth. We have already seen that they import most of their proteins
from the cytosol. Although mitochondria modify some of the lipids they import,
they do not synthesize lipids de novo; instead, their lipids have to be imported
from the ER, either directly or indirectly by way of other cell membranes. In either
case, special mechanisms are required for the transfer.
The details of how lipid distribution between different membranes is catalyzed
and regulated are not known. Water-soluble carrier proteins called phospholipid
exchange proteins (or phospholipid transfer proteins) are thought to transfer individual
phospholipid molecules between membranes, functioning much like fatty
acid binding proteins that shepherd fatty acids through the cytosol (see Figure
12–54). In addition, mitochondria are often seen in close juxtaposition to ER
membranes in electron micrographs, and specific junction complexes have been
identified that hold the ER and outer mitochondrial membrane in close proximity.
It is thought that these junction complexes provide specific contact-dependent
lipid transfer mechanisms that operate between these adjacent membranes.
Summary
The extensive ER network serves as a factory for the production of almost all of the
cell’s lipids. In addition, a major portion of the cell’s protein synthesis occurs on the
cytosolic surface of the rough ER: virtually all proteins destined for secretion or for
the ER itself, the Golgi apparatus, the lysosomes, the endosomes, and the plasma
membrane are first imported into the ER from the cytosol. In the ER lumen, the
proteins fold and oligomerize, disulfide bonds are formed, and N-linked oligosaccharides
are added. The pattern of N-linked glycosylation is used to indicate the
extent of protein folding, so that proteins leave the ER only when they are properly
folded. Proteins that do not fold or oligomerize correctly are translocated back
into the cytosol, where they are deglycosylated, polyubiquitylated, and degraded in
proteasomes. If misfolded proteins accumulate in excess in the ER, they trigger an
unfolded protein response, which activates appropriate genes in the nucleus to help
the ER cope.
Only proteins that carry a special ER signal sequence are imported into the ER.
The signal sequence is recognized by a signal-recognition particle (SRP), which
binds both the growing polypeptide chain and the ribosome and directs them to a
receptor protein on the cytosolic surface of the rough ER membrane. This binding
to the ER membrane initiates the translocation process that threads a loop of polypeptide
chain across the ER membrane through the hydrophilic pore of a protein
translocator.
Soluble proteins—destined for the ER lumen, for secretion, or for transfer to the
lumen of other organelles—pass completely into the ER lumen. Transmembrane
proteins destined for the ER or for other cell membranes are translocated part
way across the ER membrane and remain anchored there by one or more membrane-spanning
α-helical segments in their polypeptide chains. These hydrophobic
portions of the protein can act either as start-transfer or stop-transfer signals
during the translocation process. When a polypeptide contains multiple, alternating
start-transfer and stop-transfer signals, it will pass back and forth across the
bilayer multiple times as a multipass transmembrane protein.
The asymmetry of protein insertion and glycosylation in the ER establishes the
sidedness of the membranes of all the other organelles that the ER supplies with
membrane proteins.
What we don’t know
• How do nuclear import receptors
negotiate the tangled gel-like interior of
a nuclear pore complex so efficiently?
• Is the nuclear pore complex a
rigid structure or can it expand and
contract, depending on the cargo
transported?
• Sequence comparisons show that
signal sequences for an individual
protein such as insulin are quite
conserved across species, much
more so than would be expected
from our current understanding that
all that matters for their function are
general structural features such as
hydrophobicity. What other functions
might signal sequences have that
could account for their evolutionary
sequence conservation?
• How are polyribosomes on the
endoplasmic reticulum membrane
arranged so that the next initiating
ribosome will find an unoccupied
translocator?
• Why does the signal-recognition
particle have an indispensable RNA
subunit?