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

744 Chapter 13: Intracellular Membrane Traffic
as well as many secreted hydrolytic enzymes, are synthesized as inactive precursors.
Proteolysis is necessary to liberate the active molecules from these precursor
proteins. The cleavages occur in the secretory vesicles and sometimes in the extracellular
fluid after secretion. Additionally, many of the precursor proteins have an
N-terminal pro-peptide that is cleaved off to yield the mature protein. These proteins
are synthesized as pre-pro-proteins, the pre-peptide consisting of the ER signal
peptide that is cleaved off earlier in the rough ER (see Figure 12–36). In other
cases, peptide signaling molecules are made as polyproteins that contain multiple
copies of the same amino acid sequence. In still more complex cases, a variety of
peptide signaling molecules are synthesized as parts of a single polyprotein that
acts as a precursor for multiple end products, which are individually cleaved from
the initial polypeptide chain. The same polyprotein may be processed in various
ways to produce different peptides in different cell types (Figure 13–66).
Why is proteolytic processing so common in the secretory pathway? Some
of the peptides produced in this way, such as the enkephalins (five-amino-acid
neuropeptides with morphine-like activity), are undoubtedly too short in their
mature forms to be co-translationally transported into the ER lumen or to include
the necessary signal for packaging into secretory vesicles. In addition, for secreted
hydrolytic enzymes—or any other protein whose activity could be harmful inside
the cell that makes it—delaying activation of the protein until it reaches a secretory
vesicle, or until after it has been secreted, has a clear advantage: the delay
prevents the protein from acting prematurely inside the cell in which it is synthesized.
Secretory Vesicles Wait Near the Plasma Membrane Until Signaled
to Release Their Contents
Once loaded, a secretory vesicle has to reach the site of secretion, which in some
cells is far away from the TGN. Nerve cells are the most extreme example. Secretory
proteins, such as peptide neurotransmitters (neuropeptides), which will be
released from nerve terminals at the end of the axon, are made and packaged into
secretory vesicles in the cell body. They then travel along the axon to the nerve
terminals, which can be a meter or more away. As discussed in Chapter 16, motor
proteins propel the vesicles along axonal microtubules, whose uniform orientation
guides the vesicles in the proper direction. Microtubules also guide transport
vesicles to the cell surface for constitutive exocytosis.
Whereas transport vesicles containing materials for constitutive release fuse
with the plasma membrane once they arrive there, secretory vesicles in the regulated
pathway wait at the membrane until the cell receives a signal to secrete, and
they then fuse. The signal can be an electrical nerve impluse (an action potential)
or an extracellular signal molecule, such as a hormone: in either case, it leads to a
transient increase in the concentration of free Ca 2+ in the cytosol.
For Rapid Exocytosis, Synaptic Vesicles Are Primed at the
Presynaptic Plasma Membrane
Nerve cells (and some endocrine cells) contain two types of secretory vesicles. As
for all secretory cells, these cells package proteins and neuropeptides in densecored
secretory vesicles in the standard way for release by the regulated secretory
pathway. In addition, however, they use another specialized class of tiny (≈50 nm
H 2 N
signal
peptide
corticotropin
(ACTH)
α-MSH
β-lipotropin
COOH
γ-lipotropin β-MSH β-endorphin
DOCKING
FUSION
CYTOSOL
0.2 µm
Figure 13–65 Exocytosis of secretory
vesicles. The process is illustrated
schematically (top) and in an electron
micrograph that shows the release of
insulin from MBoC6 a secretory m13.66/13.66
vesicle of a
pancreatic β cell. (Courtesy of Lelio
Orci, from L. Orci, J.-D. Vassalli and
A. Perrelet, Sci. Am. 259:85–94, 1988.)
Figure 13–66 Alternative processing
pathways for the prohormone
polyprotein proopiomelanocortin. The
initial cleavages are made by proteases
that cut next to pairs of positively charged
amino acids (Lys-Arg, Lys-Lys, Arg-Lys,
or Arg-Arg pairs). Trimming reactions
then produce the final secreted products.
Different cell types produce different
concentrations of individual processing
enzymes, so that the same prohormone
precursor is cleaved to produce different
peptide hormones. In the anterior lobe
of the pituitary gland, for example, only
corticotropin (ACTH) and β-lipotropin
are produced from proopiomelanocortin,
whereas in the intermediate lobe of the
pituitary gland mainly α-melanocyte
stimulating hormone (α-MSH), γ-lipotropin,
β-MSH, and β-endorphin are produced—
α-MSH from ACTH and the other three
from β-lipotropin, as shown.