Retromer

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.

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. Mutations in retromer and its associated proteins have been linked to Alzheimer's and Parkinson's diseases.[1][2][3][4]

Retromer is a heteropentameric complex, which in humans is composed of a less defined membrane-associated sorting nexin dimer (SNX1, SNX2, SNX5, SNX6), and a vacuolar protein sorting (Vps) heterotrimer containing Vps26, Vps29, and Vps35. Although the SNX dimer is required for the recruitment of retromer to the endosomal membrane, the cargo binding function of this complex is contributed by the core heterotrimer through the binding of Vps26 and Vps35 subunits to various cargo molecules[5] including M6PR,[6] wntless,[7] SORL1 (which is also a receptor for other cargo proteins such as APP), and sortilin.[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.[9] Age-related loss of OXR1 causes retromer decline.[10]

  1. ^ Burd C, Cullen PJ (February 2014). "Retromer: a master conductor of endosome sorting". Cold Spring Harbor Perspectives in Biology. 6 (2): a016774. doi:10.1101/cshperspect.a016774. PMC 3941235. PMID 24492709.
  2. ^ Seaman MN (February 2005). "Recycle your receptors with retromer". Trends in Cell Biology. 15 (2): 68–75. doi:10.1016/j.tcb.2004.12.004. PMID 15695093.
  3. ^ Pfeffer SR (February 2001). "Membrane transport: retromer to the rescue". Current Biology. 11 (3): R109–R111. doi:10.1016/S0960-9822(01)00042-2. PMID 11231171.
  4. ^ Small SA, Petsko GA (March 2015). "Retromer in Alzheimer disease, Parkinson disease and other neurological disorders". Nature Reviews. Neuroscience. 16 (3): 126–132. doi:10.1038/nrn3896. PMID 25669742. S2CID 5166260.
  5. ^ Seaman MN (April 2004). "Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer". The Journal of Cell Biology. 165 (1): 111–122. doi:10.1083/jcb.200312034. PMC 2172078. PMID 15078902.
  6. ^ Arighi CN, Hartnell LM, Aguilar RC, Haft CR, Bonifacino JS (April 2004). "Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor". The Journal of Cell Biology. 165 (1): 123–133. doi:10.1083/jcb.200312055. PMC 2172094. PMID 15078903.
  7. ^ Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, et al. (January 2008). "The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network". Developmental Cell. 14 (1): 120–131. doi:10.1016/j.devcel.2007.12.003. PMID 18160348.
  8. ^ Canuel M, Korkidakis A, Konnyu K, Morales CR (August 2008). "Sortilin mediates the lysosomal targeting of cathepsins D and H". Biochemical and Biophysical Research Communications. 373 (2): 292–297. doi:10.1016/j.bbrc.2008.06.021. PMID 18559255.
  9. ^ Seaman MN, McCaffery JM, Emr SD (August 1998). "A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast". The Journal of Cell Biology. 142 (3): 665–681. doi:10.1083/jcb.142.3.665. PMC 2148169. PMID 9700157.
  10. ^ Wilson KA, Bar S, Dammer EB, Carrera EM, Hodge BA, Hilsabeck TA, et al. (January 2024). "OXR1 maintains the retromer to delay brain aging under dietary restriction". Nature Communications. 15 (1): 467. doi:10.1038/s41467-023-44343-3. PMC 10784588. PMID 38212606.