Vesicular transport adaptor protein

Most of the adaptor proteins are heterotetramers. In the AP complexes, there are two large proteins (~100 kD) and two smaller proteins. One of the large proteins is termed β (beta), with β1 in the AP-1 complex, β2 in the AP-2 complex, and so on. The other large protein has different designations in the different complexes. In AP-1 it is named γ (gamma), AP-2 has α (alpha), AP-3 has δ (delta), AP-4 has ε (epsilon) and AP-5 has ζ (zeta). Retromer is not closely related, has been reviewed, and its proteins will not be described here. GGAs (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) are a group of related proteins (three in humans) that act as monomeric clathrin adaptor proteins in various important membrane vesicle traffickings, but are not similar to any of the AP complexes and will not be discussed in detail in this article. Stonins (not shown in the lead figure) are also monomers similar in some regards to GGA and will not be a focus of this article. These are examples of the much larger set of cargo adaptors. == Evolutionary considerations ==

The most recent common ancestor (MRCA) of the eukaryotes must have had a mechanism for trafficking molecules between its endomembranes and organelles, and the likely identity of the adaptor complex involved has been reported. == Formation of transport vesicles ==

The best characterized type of vesicle is the clathrin coated vesicle (CCV). The formation of a COPII vesicle at the endoplasmic reticulum and its transport to the Golgi body. The involvement of the heterotetramer of COPI is similar to that of the AP/clathrin situation, but the coat of COPI is not closely related to the coats of either CCVs or COPII vesicles. AP-5 is associated with 2 proteins, SPG11 and SPG15, which have some structural similarity to clathrin, and may form the coat around the AP-5 complex, but the ultrastructure of that coat is not known. The coat of AP-4 is unknown. An almost universal feature of coat assembly is the recruitment of the various adaptor complexes to the "donor" membrane by the protein Arf1. The one known exception is AP-2, which is recruited by a particular plasma membrane lipid. Another almost universal feature of coat assembly is that the adaptors are recruited first, and they then recruit the coats. The exception is COPI, in which the 7 proteins are recruited to the membrane as a heptamer. interactions until enough interactions occur simultaneously to allow the structure to continue to develop. The last step in the formation of a transport vesicle is "pinching off" from the donor membrane. This requires energy, but even in the well studied case of CCVs, not all require dynamin. The accompanying illustration shows the case for AP-2 CCVs, however AP-1 and AP-3 CCVs do not use dynamin. == Selection of cargo molecules ==

Which cargo molecules are incorporated into a particular type of vesicle relies on specific interactions. Some of these interactions are directly with AP complexes and some are indirectly with "alternative adaptors", as shown in this diagram. The "signals" or amino acid "motifs" in the cargo proteins that interact with the adaptor proteins can be very short. For example, one well-known example is the dileucine motif, in which a leucine amino acid (aa) residue is followed immediately by another leucine or isoleucine residue. An even simpler example is the tyrosine based signal, which is YxxØ (a tyrosine residue separated by 2 aa residues from another bulky, hydrophobic aa residue). The accompanying figure shows how a small part of a protein can interact specifically with another protein, so these short signalling motifs should not be surprising. The sort of sequence comparisons used, in part, to define these motifs. In some cases, post-translational modifications, such as phosphorylations (shown in the figure) are important for cargo recognition. == Diseases ==

Adaptor diseases have been reviewed. Retromer is involved in recycling components of the plasma membrane. The importance of that recycling at a synapse is hinted at in one of the figures in the gallery. There are at least 3 ways in which retromer dysfunction can contribute to brain disorders, including Alzheimer and Parkinson diseases. COPII is linked to cranio-lenticulo-sutural dysplasia. One of the GGA proteins may be involved in Alzheimer's disease. == Gallery ==