Vesicular transport adaptor proteins are proteins involved in forming complexes that function in the trafficking of molecules from one subcellular location to another. These complexes concentrate the correct cargo molecules in vesicles that bud or extrude off of one organelle and travel to another location, where the cargo is delivered. While some of the details of how these adaptor proteins achieve their trafficking specificity has been worked out, there is still much to be learned.
There are several human disorders associated with defects in components of these complexes including Alzheimer's and Parkinson's diseases.
The proteins
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). The two smaller proteins are a medium subunit named μ (mu ~50 kD) and a small subunit σ (sigma ~20 kD), and named 1 through 5 corresponding to the 5 AP complexes. Components of COPI (cop one) a coatomer, and TSET (T-set) a membrane trafficking complex have similar heterotetramers of the AP complexes.
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 also not be discussed in detail in this article.
PTBs are protein domains that include NUMB, DAB1 and DAB2. Epsin and AP180 in the ANTH domain are other adaptor proteins that have been reviewed.
An important transport complex, COPII, was not shown in the lead figure. The COPII complex is a heterohexamer, but not closely related to the AP/TSET complexes. The individual proteins of the COPII complex are called SEC proteins, because they are encoded by genes identified in secretory mutants of yeast. One especially interesting aspect of COPII is that it can form typical spherical vesicles and tubules to transport large molecules like collagen precursors, which cannot fit inside typical spherical vesicles. COPII structure has been discussed in an open article 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. It is believed that the MRCA had 3 proteins involved in trafficking and that they formed a heterotrimer. That heterotrimer next "dimerized" to form a 6 membered-complex. The individual components further changed into the current complexes, in the order shown, with AP1 and AP2 being the last to diverge.
In addition, one component of TSET, a muniscin also known as the TCUP protein, appears to have evolved into part of the proteins of opisthokonts (animals and fungi). Parts of the AP complexes have evolved into parts of the GGA and stonin proteins. There is evidence indicating that parts of the nuclear pore complex and COPII may be evolutionarily related.
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.