section 25.10
Protein Synthesis
- TSSC-e
Signal recognition particle
pan oa
Membrane ol
FIGURE 25-16
Signal hypothesis for the synthesis of secretory and membrane proteins. Shortly after initiation of protein synthesis, the
amino-terminal sequence of the polypeptide chain binds a signal recognition protein, which then binds to a docking
protein. The signal peptide is released from the signal recognition protein as the ribosome binds to a ribosome receptor,
which is adjacent to a pore. Translation continues with the signal peptide passing through the pore. Once through the
endoplasmic reticulum, the signal sequence is excised by the signal peptidase within the vesicle. When protein synthesis
is completed, the protein remains within the vesicle and the ribosome is released.
In summary, the following events take place. When the
predominant portion of the protein is synthesized and mi-
grates in the endoplasmic reticulum, the signal sequence
is removed by proteolytic cleavage. The finished protein,
which is sequestered on the cisternal side of the endoplas-
mic reticulum, undergoes many posttranslational modifi-
cations, one of which is the addition of a series of car-
bohydrate residues to form glycoproteins (Chapter 16).
Glycoproteins are transported to the Golgi complex, where
further modification of the carbohydrate residues occurs.
The finished glycoproteins are then packaged into lyso-
somes, peroxisomes, or secretory vesicles. The last fuses
with the plasma membrane, discharging its contents into
the extracellular fluid. Defects in compartmentation pro-
cesses may lead to mislocation of the proteins and cause
deleterious effects. Many proteins that are destined for
various organelles (e.g., mitochondria) are not routed
through endoplasmic reticulum and the Golgi complex.
These proteins are made on cytosolic polysomes. They
possess presequences at amino terminal ends that target
them to receptors on appropriate organelles. Import of pro-
teins into cell organelles is aided by
chaperone proteins
(Chapter 4).
Compartment Disorders
Two defects of compartmentation are known. One,
I-cell disease
(Chapter 16), is characterized by
mislocalization of lysosomal enzymes (acid hydrolases).
These glycoproteins lack mannose-
-phosphate residues,
and consequently they are secreted into extracellular fluids
instead of being sequestered into lysosomal vesicles. The
-phosphate serves as a marker that allows the
enzymes to bind with mannose-
-phosphate receptors that
direct the enzymes into the vesicles to be packaged into
lysosomes. The lysosomal enzymes in the extracellular
fluid bring about indiscriminate destruction of tissues.
The second example of the compartmentation defect
a i -antitrypsin deficiency
(also known as
i -proteinase
inhibitor deficiency). The defect in this disorder is almost
exactly the opposite of that in I-cell disease, i.e., I-cell
disease is a disorder of a defect in (intracellular) reten-
tion of proteins and
i -antitrypsin deficiency is a defect in
the secretion of a protein,
i-Antitrypsin (c*q-AT) consists
of a single polypeptide chain of 394 amino acid residues
with three oligosaccharide side chains (Figure 25-17), all
of which are attached to asparagine residues. It contains
sheets and eight
helices. It has an overall mole-
cular weight of 51,000. It is a polar molecule and readily
migrates into tissue fluids. It is synthesized in hepatocytes
and secreted into the plasma, where it has a half-life of
days. Its normal serum concentration is 150-200 mg/dL.
Although the presence of oq-AT has been noted in other
cell types, the primary source in plasma is the hepatocyte.
oq-AT does not possess a propeptide but does contain a
24-residue signal peptide, which is eliminated during its
passage through the endoplasmic reticulum,
i - AT is a de-
fense protein, and its synthesis and release into circulation
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