8. ER proteins are retrieved from the Golgi

25.7 Protein localization depends on further signals

Key terms defined in this section
Lysosomes are small bodies, enclosed by membranes, that contain hydrolytic enzymes in eukaryotic cells.

Various types of signals influence transport through the ER-Golgi system. A protein that has no special signals will presumably enter vesicles at a rate determined by its concentration in the compartment, and may move in the anterograde direction by bulk flow. However, most proteins appear to have specific signals that facilitate or retard transport.




Figure 25.22 A transport signal in a trans- membrane cargo protein interacts with an adaptor protein.


Figure 25.23 A transport signal in a luminal cargo protein interacts with a transmembrane receptor that interacts with an adaptor protein.

A typical cargo protein has a transport signal that is responsible for its entry into budding vesicles. Figure 25.22 shows that the transport signal in a transmembrane protein is usually a region in its cytoplasmic domain that binds to an adaptor protein of the vesicle coat. Figure 25.23 shows that the transport signal in a soluble cargo protein (for example, a secreted protein that passes through the lumen) is a region that binds to the lumenal domain of a transmembrane cargo receptor, which in turn has an cytoplasmic domain that binds an adaptor protein. Interaction between the cargo and the coat thus directly or indirectly determines specificity of transport. Such mechanisms control anterograde transport from the ER to the cell surface and other destinations.


A protein may be prevented from leaving a compartment by a retention signal. Such signals are often found in transmembrane regions, perhaps because aggregation between them creates a structure that is too large to be incorporated into a budding vesicle.


We have detailed information about several types of signal: a conformation that is required for proteins to be internalized by endocytosis; an amino acid sequence that targets proteins to the ER; and a modification that targets proteins to lysosomes (small membranous bodies, where proteins are degraded; see later).


Internalization of receptors via coated pits requires information in their cytoplasmic tails. The sequence for internalization is usually a short amino acid motif located near the C-terminus. Typically it makes a tight turn in the structure and exposes a tyrosine. Two signals of this sort are NPXY and YXRF. Although these are a basic signals for internalization, other sequences in the cytoplasmic tail influence the efficiency (Collawn et al., 1990).




Figure 25.5 Processing for a complex oligosaccharide occurs in the Golgi and trims the original preformed unit to the inner core consisting of 2 N-acetyl-glucosamine and 3 mannose residues. Then further sugars can be added, in the order in which the transfer enzymes are encountered, to generate a terminal region containing N-acetyl-glucosamine, galactose, and sialic acid.

Enzymes that will be transported to lysosomes are recognized as targets for high mannose glycosylation, and are trimmed in the ER as described in Figure 25.5. Then mannose-6-phosphate residues are generated by a two-stage process in the Golgi. First the moiety N-acetyl-glucosamine-1-phosphate is added to the 6 position of mannose by GlcNAc-phosphotransferase; then a glucosaminidase removes the N-acetyl-glucosamine (GlcNAc).


The action of the phosphotransferase provides the critical step in marking a protein for lysosomal transport. It occurs early in ER-Golgi transfer, possibly between the ER and the cis Golgi. The basis for the enzyme’s specificity is its ability to recognize a structure that is common to lysosomal proteins. The structure consists of two short sequences, which are separated in the primary sequence, but form a common surface in the tertiary structure. Each of these sequences has a crucial lysine residue. The nature of this signal explains how proteins with little identity of sequence may share a common pathway for localization (Griffiths et al., 1988).


Lysosomal proteins continue to be transported along the Golgi stacks until they encounter receptors for mannose-6-phosphate. Recognition of mannose-6-phosphate targets a protein for transport in a coated vesicle to the lysosome. This final stage of sorting for the lysosome occurs in the trans Golgi, where the proteins are collected by specific transport vesicles that are coated with clathrin. The vesicles transport the lysosomal proteins to the late endosome, where they join the pathway for movement to the lysosome. A single pool of mannose-6-phosphate receptors is probably used for directing proteins to the lysosome whether they are newly synthesized or endocytosed. Most of the receptors in fact are located on endosomes, where they could recognize endocytosed proteins (for review see von Figura and Hasilik, 1986; Kornfeld and Mellman, 1989).




Reviews
Kornfeld, S. and Mellman, I. (1989). The biogenesis of lysosomes. Ann. Rev. Cell Biol. 5, 483-525.
von Figura, K. and Hasilik, A. (1986). Lysosomal enzymes and their receptors. Ann. Rev. Biochem 55, 167-193.

Research
Collawn, J. F. et al. (1990). Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis. Cell 63, 1061-1072.
Griffiths, G., Hoflack, B., Simons, K., Mellman, I., and Kornfeld, S. (1988). The mannose 6-phosphate receptor and the biogenesis of lysosomes. Cell 52, 329-341.



Genes VII
Genes VII
ISBN: B000R0CSVM
EAN: N/A
Year: 2005
Pages: 382

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