Retromer

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Schematic representation of a retromer

A retromer is a protein complex that is involved in the transport of membrane proteins in vesicles between endosomes and the trans -Golgi network .

construction

In mammalian cells, retromers consist of five different proteins (a heteropentamer ), including a heterodimer from two of the sorting Nexins SNX1 , SNX2 , SNX5 and SNX6 and a heterotrimer from Vps26 , Vps29 and Vps35 ( vacuolar protein sorting ). They serve simultaneously as a membrane-stabilizing protein framework and as a sorting signal. Retromers are involved in transport within the cell, in signal transduction during development and in the formation of lysosomes . In polarized cells such as epithelial cells and neurons , the retromer is also used for transcytosis . In yeast , a retromer consists of the five proteins Vps5, Vps17, Vps26, Vps29 and Vps35. The subunit Vps35 binds various cellular membrane proteins for sorting. A heterodimer made from SNX1 or SNX2 with SNX5 or SNX6 induces the bulging of the endosome membrane into a tubular membrane structure from which transport vesicles are tied off. The constriction of a vesicle from the tubular protuberance is mediated not only by actin polymerization but also by Dynamin-II or EHD1 .

Sorting

The sorting on the retromer determines whether a bound membrane protein remains in the endosome and later degradation in the lysosome or whether it is transported from the endosome into the trans-Golgi network near the cell membrane . Vps 35 binds the WASH protein complex (more precisely FAM21 and WASH1 ). Sorting into different vesicles requires sorting the membrane proteins into different areas of the endosome membrane, where a tubular protuberance of the endosome membrane takes place to form transport vesicles. The membrane proteins to be sorted bind to the trimeric subunit Vps35-Vps29-Vps26 of the retromer (the cargo-selective complex , CSC).

The proteins in the endosome membrane are sorted by binding the WASH complex, which activates Arp2 / 3 on the cytosolic side of the endosome membrane . This creates actin filaments that mediate a sideways movement of the retromer and its loading (bound membrane proteins) in the endosome membrane. The binding of the trimeric subunit Vps35-Vps29-Vps26 to the membrane proteins to be sorted takes place in their cytosolic regions. GTP -activated Rab7 , clathrin , clathrin adapter proteins and other proteins then binds .

Assorted proteins

More than 100 membrane proteins are sorted by the retromer. Disturbance of the retro-merger significantly reduces the amount of these proteins in the cell membrane. The sorted proteins include M6PR (synonym CIMPR), GPR177 , Sortilin 1 , DMT1-II (synonym Slc11a2), Wntless (synonym MIG-14), Crumbs and a still unknown protein that transports amyloid precursor protein .

Pathogens

Bacteria living intracellularly in vesicles have developed various mechanisms to inhibit vesicle transport. The RidL protein from Legionella pneumophila inhibits the retromere, while IncE from Chlamydia trachomatis inhibits SNX5 / 6.

Applications

Retromers are being investigated for the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease .

Individual evidence

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