The Fifth Adaptor Protein Complex

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Abstract
Adaptor protein (AP) complexes sort cargo into vesicles for transport from one membrane compartment of the cell to another. Four distinct AP complexes have been identified, which are present in most eukaryotes. We report the existence of a fifth AP complex, AP-5. Tagged AP-5 localises to a late endosomal compartment in HeLa cells. AP-5 does not associate with clathrin and is insensitive to brefeldin A. Knocking down AP-5 subunits interferes with the trafficking of the cation-independent mannose 6-phosphate receptor and causes the cell to form swollen endosomal structures with emanating tubules. AP-5 subunits can be found in all five eukaryotic supergroups, but they have been co-ordinately lost in many organisms. Concatenated phylogenetic analysis provides robust resolution, for the first time, into the evolutionary order of emergence of the adaptor subunit families, showing AP-3 as the basal complex, followed by AP-5, AP-4, and AP-1 and AP-2. Thus, AP-5 is an evolutionarily ancient complex, which is involved in endosomal sorting, and which has links with hereditary spastic paraplegia. Adaptor protein (AP) complexes facilitate the trafficking of cargo from one membrane compartment of the cell to another by recruiting other proteins to particular types of vesicles. For over 10 years, it has been assumed that there are four, and only four, distinct AP complexes in eukaryotic cells. We report the existence of a fifth AP complex, AP-5. Immunolocalisation and RNAi knockdown experiments both indicate that AP-5 is involved in trafficking proteins from endosomes towards other membranous compartments. There are genetic links between AP-5 and hereditary spastic paraplegia, a group of human genetic disorders characterised by progressive spasticity in the lower limbs. Phylogenetic analyses indicate that AP-5 was already present in the last eukaryotic common ancestor over a billion years ago.

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