VPS35
Description
The VPS35 (VPS35 retromer complex component) is a protein-coding gene located on chromosome 16.
Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures (e.g., endosomes, lysosomes, vacuoles) and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.
== Gene == In humans, VPS35 is transcribed on chromosome 16q11.2 where is spans about 29.6 kilobases and contains 17 exons. It is evolutionarily conserved and required for survival, as mouse knockout studies have demonstrated embryonic lethality. VPS35 levels peak at postnatal days 10-15 and then decline to a low, stable level throughout adulthood. RNA expression of VPS35 is ubiquitous throughout the body, but are higher in the brain, heart, gonads, spleen, and skeletal muscle, and lower in the lung, liver, kidney, and blood leukocytes.
== Protein == VPS35 was first identified in Saccharomyces cerevisiae from a study investigating the formation of lysosome-like vacuoles and sorting of vacuolar proteins.
VPS35 is a key component of the retromer cargo-selective complex (CSC), which plays a crucial role in regulating the sorting and trafficking of transmembrane proteins within cells. The CSC acts as a hub for other proteins, ensuring proper protein delivery to their destinations and preventing their degradation in lysosomes. VPS35's involvement in this process is critical for various cellular functions, including the retrograde transport of cargo proteins from endosomes to the Golgi apparatus, the recycling of proteins back to the plasma membrane, and the localization of specific proteins within endosomes. Notably, VPS35 interacts with a variety of proteins, including RAB7A, SNX3, IGF2R, SLC11A2, WASHC2, and TBC1D5, to facilitate these diverse functions. VPS35 also contributes to the regulation of transcytosis, the process by which proteins are transported across epithelial cells. Mutations in VPS35 have been linked to malfunctions in autophagy, potentially contributing to neurodegenerative diseases.
VPS35 is also known as MEM3, PARK17.
