Retromer

Retromer is a complex of proteins that has been shown to be important in recycling transmembrane receptors from endosomes to the trans-Golgi network (TGN) and directly back to the plasma membrane.

[8] Early study on sorting of acid hydrolases such as carboxypeptidase Y (CPY) in S. cerevisiae mutants has led to the identification of retromer in mediating the retrograde trafficking of the pro-CPY receptor (Vps10) from the endosomes to the TGN.

Humans have two orthologs of VPS26: VPS26A, which is ubiquitous, and VPS26B, which is found in the central nervous system, where it forms a unique retromer that is dedicated to direct recycling of neuronal cell surface proteins such as APP back to the plasma membrane with the assistance of the cargo receptor SORL1.

[15] Retromer plays a central role in the retrieval of several different cargo proteins from the endosome to the trans-Golgi network, or for direct recycling back to the cell surface.

[4] Dysfunction of this branch of the retromer recycling pathway causes endosomal protein traffic jams [26] that are linked to Alzheimer’s disease.

[27][28] It has been suggested that recycling dysfunction is the “fire” that drives the common form of Alzheimer’s, leading to the production of amyloid and tau tangle “smoke”.

Model of the retromer heteropentameric complex ( VPS26 in green; VPS35 in orange, and VPS29 in red). The retromer forms a polymeric network arc on the outside (cytoplasmic side) of the endosome tubule. Inside the tubule, the cargo receptor SORL1 , forms its own network and binds protein cargo for trafficking. SORL1 connects to retromer on the outside via a transmembrane helix and a short C-terminal tail that binds VPS26. Model built based on structural data by Brett Collins and Yu Kitago.
Ribbon diagram of the retromer heterotrimeric complex comprising the proteins VPS26 (green), VPS35 (orange) and VPS29 (red). On the endosomal membrane, this heterotrimer forms an arch-shaped dimer via interaction of two VPS35 molecules (see next image). [ 11 ]
CryoET structure of retromer heterotrimer dimer on the tubular endosome membrane in surface rendering. VPS26 is in green, VPS35 in orange, and VPS29 in red. The heterotrimer forms a characteristic dimeric arch. The grey SNX protein aids in tubulation and retromer membrane binding. [ 11 ]