Retromer

Retromer is a protein complex involved in the transport of proteins within eukaryotic cells. It plays a critical role in the sorting of transmembrane proteins, particularly in the retrieval of certain proteins from endosomes back to the Golgi apparatus or to the plasma membrane. The retromer complex is essential for various cellular processes, including the regulation of enzyme activity, the recycling of receptors, and the maintenance of cell surface protein composition.

Structure

The retromer complex is composed of two main subcomplexes: the cargo-selective complex (CSC) and the vacuolar protein sorting (VPS) complex. The CSC typically consists of the VPS26, VPS29, and VPS35 proteins, which are responsible for recognizing and binding to the cargo proteins to be transported. The VPS complex, on the other hand, includes VPS5 and VPS17 in yeast (or their mammalian homologs, SNX1/SNX2 and SNX5/SNX6, respectively), and it is involved in the formation of tubules that aid in the transport of cargo proteins.

Function

Retromer has a pivotal role in the retrograde transport of proteins from endosomes to the Golgi apparatus or the plasma membrane. This process is crucial for the recycling of receptors, such as the mannose 6-phosphate receptor (MPR), which is involved in the trafficking of lysosomal enzymes. By retrieving these receptors from endosomes, the retromer prevents their degradation in lysosomes and ensures their availability for further rounds of transport. Additionally, retromer is involved in the Wnt signaling pathway, where it regulates the sorting and processing of the Wnt receptor, LRP6.

Clinical Significance

Mutations in the genes encoding retromer components have been linked to various human diseases. For example, defects in VPS35 are associated with late-onset Parkinson's disease, highlighting the importance of retromer in neuronal function and survival. Furthermore, alterations in retromer function have been implicated in Alzheimer's disease, due to its role in the trafficking and processing of the amyloid precursor protein (APP), which is involved in the production of amyloid-beta, a key component of Alzheimer's disease pathology.

Research Directions

Ongoing research aims to further elucidate the molecular mechanisms by which retromer mediates protein sorting and trafficking. Understanding these processes at a detailed level may provide insights into the development of therapeutic strategies for diseases associated with retromer dysfunction. Additionally, the exploration of retromer's role in other cellular processes and signaling pathways continues to be an active area of investigation.

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  Retromer and SORL1 on tubular endosome
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  Retromer heterotrimer ribbon rendering
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  Retromer 6H7W