Last modified 19th May '95 © Birkbeck College 1995
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Targeting and Transport of Proteins
The destination of proteins synthesized by ribosomes obviously depends on their
function. The following applies to eukaryotic cells:
- proteins synthesized by ribosomes on the rough endoplasmic reticulum (E.R.) may
be "injected" across the plasma membrane into the lumen and thence exported
(secreted by the cell) to the extracellular environment
- integral membrane proteins (see
previous chapter) remain in the plasma membrane (or the membranes of
- other proteins are directed to specific organelles where they function
- proteins synthesized by free ribosomes remain in the cytoplasm
Refer to the page on transport across the E.R. membrane
for a description of how proteins destined for secretion are "tagged" so
that they enter the endoplasmic reticulum.
The Maturation Pathway
Mutation studies have indicated that once synthesized, the secreted proteins are
situated in various organelles and vesicles in the following order:
The coated vesicles which bud from the E.R. have their membranes enclosed by a
polyhedral clathrate ("cage-like") structure, consisting of an association of
triskelions. The triskelions are flexible, "three-legged" protein complexes
composed of the protein clathrin and its associated proteins. The sides
of the polyhedron are formed by overlapping "legs", and are about 150Å long.
The faces of the framework are pentagonal (always 12) and hexagonal (variable
number)- similar constraints of symmetry apply as in the "spherical"
- rough endoplasmic reticulum
- coated vesicles
- condensing vesicles
- mature secretory vesicles
- followed by exocytosis
The condensing vesicles, also coated, bud off from the Golgi apparatus and are
converted to mature secretory vesicles by concentration of their contents.
Some types of cells continuously secrete proteins in these vesicles, e.g serum
collagens, while in others the proteins are stored in vesicles
awaiting a hormone signal to trigger their exocytosis. The secretory vesicles
of pancreatic exocrine cells are called zymogen granules as the proteins
in them are the inactive forms (zymogens) of the digestive enzymes.
Proteins are glycosylated in the rough E.R. Further modifications of the
carbohydrate chains occurs in the Golgi apparatus. This process serves to label
various types of proteins to direct them to their correct destinations (see
below). A page on glycosylation of proteins will follow.
Proteins Directed to Organelles
Other non-cytoplasmic proteins are synthesized by the ribosomes on the rough E.R.
besides those which are destined for secretion. These include integral membrane
proteins, not only in the plasma membane but also in the membranes of other
organelles such as the smooth E.R. Lysosomal enzymes are also synthesized
by the rough E.R. ribosomes. (Here are notes on
The oligosaccharide added to lysosomal enzymes in the rough E.R. lumen is the
same as that which is added to secretory proteins. However,
one or more mannose residues of the lysosomal enzymes are phosphorylated. This
acts as a signal which leads to the enzymes eventually entering the lysosomes.
This phosphorylation occurs in two steps, catalyzed first by N-acetylglucosamine
phosphotransferase, and then by a phosphodiesterase, giving a mannose 6-phosphate
residue. These enzymes are located in the Golgi apparatus.
The lumenal face of the Golgi membrane has a receptor for mannose 6-phosphate.
It is thought that regions of this membrane including the receptors and bound
glycosylated enzyme bud off to form transport vesicles which carry their contents
to sorting vesicles. Sorting vesicles are acidic (pH 5), which is not
favourable for binding of the mannose-6-phosphate receptor and ligand. The
released lysosomal enzymes then have their mannose 6-phosphate residues
dephosphorylated, so that the enzyme cannot re-bind to the receptor. Vesicles
containing the enzymes but devoid of the receptor then bud from the sorting
vesicle and fuse with lysosomes.
Read about the role of cathepsin in Baldwin et al. (1993).
cathepsin D complexed with pepstatin; two enzymes
in the asymmetric unit in each case. Both enzymes consist of two chains, due to
- Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K. and Watson, J.D.
(1983) Molecular Biology of The Cell, Garland Publishing, New York pp. 343-345
- Baldwin, E.T., Bhat, T.N., Gulnik, S., Hosur, M.V., Sowder, R.C., Cachau, R.E.,
Collind, J., Silva, A.M. and Erickson, J.W. (1993) Crystal structures of native
and inhibited forms of human cathepsin D: implications for lysosomal targeting
and drug design Proc. Natl. Acad. Sci. USA 90 6796
- Darnell, J., Lodish, H. and Baltimore, D. (1986) Molecular Cell Biology,
W.H. Freeman & Co., New York, pp. 947-949
- Stryer, L., (1981) Biochemistry, W.H. Freeman & Co., New York pp. 712-714
- Voet, D. and Voet, J.G. (1990) Biochemistry, John Wiley & Sons, New York
, pp. 299-300
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