Retromer

Last updated
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 and SORL1 on tubular endosome.png
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]

Contents

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]

Structure

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). Retromer heterotrimer ribbon rendering.png
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).
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. Retromer 6H7W.png
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.

The retromer complex is highly conserved: homologs have been found in C. elegans , mouse and human. The retromer complex consists of 5 proteins in yeast: Vps35p, Vps26p, Vps29p, Vps17p, Vps5p. The mammalian retromer consists of Vps26, Vps29, Vps35, SNX1 and SNX2, and possibly SNX5 and SNX6. [12] It is proposed to act in two subcomplexes: (1) A cargo recognition heterotrimeric complex that consist of Vps35, Vps29 and Vps26, and (2) SNX-BAR dimers, which consist of SNX1 or SNX2 and SNX5 or SNX6 that facilitate endosomal membrane remodulation and curvature, resulting in the formation of tubules/vesicles that transport cargo molecules to the trans-golgi network (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. [13]

Function

The retromer complex has been shown to mediate retrieval of various transmembrane receptors, such as the cation-independent mannose 6-phosphate receptor, functional mammalian counterparts of Vps10 such as SORL1, and the Wnt receptor Wntless. [14] Retromer is required for the recycling of Kex2p and DPAP-A, which also cycle between the trans-Golgi network and a pre-vacuolar (yeast endosome equivalent) compartment in yeast. It is also required for the recycling of the cell surface receptor CED-1, which is necessary for phagocytosis of apoptotic cells. [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. However, it is clear that there are other complexes and proteins that act in this retrieval process. So far it is not clear whether some of the other components that have been identified in the retrieval pathway act with retromer in the same pathway or are involved in alternative pathways. Recent studies have implicated retromer sorting defects in Alzheimer's disease [16] [17] and late-onset Parkinson disease [18]

Retromer also seems to play a role in Hepatitis C Virus replication. [19]

Retrograde trafficking and direct recycling

Retrograde trafficking to the trans-Golgi network

The association of the Vps35-Vps29-Vps26 complex with the cytosolic domains of cargo molecules on endosomal membranes initiates the activation of retrograde trafficking and cargo capture. [20] The nucleation complex is formed through the interaction of VPS complex with GTP-activated Rab7 [21] with clathrin, clathrin-adaptors and various binding proteins. [22]

The SNX-BAR dimer enters the nucleation complex via direct binding or lateral movement on endosomal surface. The increased level of Retromer SNX-BARs causes a conformational switch to a curvature-inducing mode which initiates membrane tubule formation. [23] [24] Once the cargo carriers are matured, the carrier scission is then catalyzed by dynamin-II or EHD1, [25] together with the mechanical forces generated by actin polymerization and motor activity.

The cargo carrier is transported to the TGN by motor proteins such as dynein. Tethering of the cargo carrier to the recipient compartment is thought to lead to the uncoating of the carrier, which is driven by ATP-hydrolysis and Rab7-GTP hydrolysis. Once released from the carrier, the Vps35-Vps29-Vps26 complex and the SNX-BAR dimers get recycled back onto the endosomal membranes.

Direct recycling back to the cell surface

The other function of retromer is the recycling of protein cargo directly back to the plasma membrane. [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”. [29]

See also

Related Research Articles

<span class="mw-page-title-main">Endosome</span> Vacuole to which materials ingested by endocytosis are delivered

Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can follow this pathway all the way to lysosomes for degradation or can be recycled back to the cell membrane in the endocytic cycle. Molecules are also transported to endosomes from the trans Golgi network and either continue to lysosomes or recycle back to the Golgi apparatus.

<span class="mw-page-title-main">Vesicular transport adaptor protein</span>

Vesicular transport adaptor proteins are proteins involved in forming complexes that function in the trafficking of molecules from one subcellular location to another. These complexes concentrate the correct cargo molecules in vesicles that bud or extrude off of one organelle and travel to another location, where the cargo is delivered. While some of the details of how these adaptor proteins achieve their trafficking specificity has been worked out, there is still much to be learned.

The coatomer is a protein complex that coats membrane-bound transport vesicles. Two types of coatomers are known:

<span class="mw-page-title-main">SORL1</span> Protein-coding gene in the species Homo sapiens

Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.

<span class="mw-page-title-main">SNX1</span> Protein-coding gene in the species Homo sapiens

Sorting nexin-1 is a protein that in humans is encoded by the SNX1 gene. The protein encoded by this gene is a sorting nexin. SNX1 is a component of the retromer complex.

<span class="mw-page-title-main">Sortilin 1</span> Protein-coding gene in the species Homo sapiens

Sortilin (SORT1) is a protein that in humans is encoded by the SORT1 gene on chromosome 1. This protein is a type I membrane glycoprotein in the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors. While it is ubiquitously expressed in many tissues, sortilin is most abundant in the central nervous system. At the cellular level, sortilin functions in protein transport between the Golgi apparatus, endosome, lysosome, and plasma membrane, leading to its involvement in multiple biological processes such as glucose and lipid metabolism as well as neural development and cell death. Moreover, the function and role of sortilin is now emerging in several major human diseases such as hypertension, atherosclerosis, coronary artery disease, Alzheimer’s disease, and cancer. The SORT1 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

BLOC-1 or biogenesis of lysosome-related organelles complex 1 is a ubiquitously expressed multisubunit protein complex in a group of complexes that also includes BLOC-2 and BLOC-3. BLOC-1 is required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules. These organelles are called LROs which are apparent in specific cell-types, such as melanocytes. The importance of BLOC-1 in membrane trafficking appears to extend beyond such LROs, as it has demonstrated roles in normal protein-sorting, normal membrane biogenesis, as well as vesicular trafficking. Thus, BLOC-1 is multi-purposed, with adaptable function depending on both organism and cell-type.

<span class="mw-page-title-main">STX6</span> Protein-coding gene in the species Homo sapiens

Syntaxin-6 is a protein that in humans is encoded by the STX6 gene.

<span class="mw-page-title-main">VAMP3</span> Protein-coding gene in the species Homo sapiens

Vesicle-associated membrane protein 3 is a protein that in humans is encoded by the VAMP3 gene.

<span class="mw-page-title-main">VPS35</span> Protein-coding gene in the species Homo sapiens

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 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.

<span class="mw-page-title-main">SNX2</span> Protein-coding gene in the species Homo sapiens

Sorting nexin-2 is a protein that in humans is encoded by the SNX2 gene.

<span class="mw-page-title-main">VPS26A</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting-associated protein 26A is a protein that in humans is encoded by the VPS26A gene.

<span class="mw-page-title-main">RAB11FIP5</span> Protein-coding gene in the species Homo sapiens

Rab11 family-interacting protein 5 is a protein that in humans is encoded by the RAB11FIP5 gene.

<span class="mw-page-title-main">VPS29</span> Protein-coding gene in the species Homo sapiens

VPS29 is a human gene coding for the vacuolar protein sorting protein Vps29, a component of the retromer complex.

<span class="mw-page-title-main">SNX5</span> Protein-coding gene in the species Homo sapiens

Sorting nexin-5 is a protein that in humans is encoded by the SNX5 gene.

<span class="mw-page-title-main">RAB11B</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-11B is a protein that in humans is encoded by the RAB11B gene. Rab11b is reported as most abundantly expressed in brain, heart and testes.

Sorting Nexin 6 also known as SNX6 is a well-conserved membrane-associated protein belonging to the sorting nexin family that is a component of the retromer complex. The protein contains a coiled-coil domain at its C terminus and a PX domain at its N terminus. Binding to PIM1 causes translocation to the nucleus. SNX6 has been shown to associate with TRAF4.

<span class="mw-page-title-main">Cation-dependent mannose-6-phosphate receptor</span> Protein-coding gene in the species Homo sapiens

In the fields of biochemistry and cell biology, the cation-dependent mannose-6-phosphate receptor (CD-MPR) also known as the 46 kDa mannose 6-phosphate receptor is a protein that in humans is encoded by the M6PR gene.

<span class="mw-page-title-main">STX10</span> Protein-coding gene in the species Homo sapiens

Syntaxin-10 (STX10) is a SNARE protein that is encoded by the STX10 gene. This protein is found in most vertebrates but is noticeably absent from mice. As with other SNARE proteins, STX10 facilitates vesicle fusion and thus is important for intracellular trafficking of proteins and other cellular components. More specifically, STX10 has been implicated in endosome to Golgi trafficking of the mannose 6-phosphate receptor and glucose transporter type 4.

<span class="mw-page-title-main">SNX8</span> Protein

The SNX8 is a sorting nexin protein involved in intracellular molecular traffic from the early endosomes to the TGN. It is suggested that it acts as an adaptor protein in events related to immune response and cholesterol regulation, for example. As a protein of the SNXs family, the SNX8 is formed of 465 aminoacids and presents a BAR-domain and a PX-domain which are very relevant in relation to its functions. Furthermore, SNX8 study is motivated by its medical significance in relation to diseases such as Alzheimer's Disease, cancer, neurodevelopmental malformations and to its role in fighting against viral infections.

References

  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. 1 2 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.
  11. 1 2 PDB: 6H7W ​; Kovtun O, Leneva N, Bykov YS, Ariotti N, Teasdale RD, Schaffer M, et al. (September 2018). "Structure of the membrane-assembled retromer coat determined by cryo-electron tomography". Nature. 561 (7724): 561–564. doi:10.1038/s41586-018-0526-z. PMC   6173284 . PMID   30224749.
  12. ↑ Wassmer T, Attar N, Bujny MV, Oakley J, Traer CJ, Cullen PJ (January 2007). "A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer". Journal of Cell Science. 120 (Pt 1): 45–54. doi: 10.1242/jcs.03302 . PMID   17148574.
  13. ↑ Simoes S, Guo J, Buitrago L, Qureshi YH, Feng X, Kothiya M, et al. (December 2021). "Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling". Cell Reports. 37 (13): 110182. doi:10.1016/j.celrep.2021.110182. PMC   8792909 . PMID   34965419.
  14. ↑ Eaton S (January 2008). "Retromer retrieves wntless". Developmental Cell. 14 (1): 4–6. doi: 10.1016/j.devcel.2007.12.014 . PMID   18194646.
  15. ↑ Chen D, Xiao H, Zhang K, Wang B, Gao Z, Jian Y, et al. (March 2010). "Retromer is required for apoptotic cell clearance by phagocytic receptor recycling". Science. 327 (5970): 1261–1264. Bibcode:2010Sci...327.1261C. doi: 10.1126/science.1184840 . PMID   20133524. S2CID   6923948.
  16. ↑ Sadigh-Eteghad S, Askari-Nejad MS, Mahmoudi J, Majdi A (January 2016). "Cargo trafficking in Alzheimer's disease: the possible role of retromer". Neurological Sciences. 37 (1): 17–22. doi:10.1007/s10072-015-2399-3. PMID   26482054. S2CID   20019740.
  17. ↑ Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, et al. (May 2008). "Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation". Proceedings of the National Academy of Sciences of the United States of America. 105 (20): 7327–7332. Bibcode:2008PNAS..105.7327M. doi: 10.1073/pnas.0802545105 . PMC   2386077 . PMID   18480253.
  18. ↑ Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, Offman MN, et al. (July 2011). "A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease". American Journal of Human Genetics. 89 (1): 168–175. doi:10.1016/j.ajhg.2011.06.008. PMC   3135812 . PMID   21763483.
  19. ↑ Yin P, Hong Z, Yang X, Chung RT, Zhang L (February 2016). "A role for retromer in hepatitis C virus replication". Cellular and Molecular Life Sciences. 73 (4): 869–881. doi:10.1007/s00018-015-2027-7. PMID   26298293. S2CID   3617566.
  20. ↑ Nothwehr SF, Ha SA, Bruinsma P (October 2000). "Sorting of yeast membrane proteins into an endosome-to-Golgi pathway involves direct interaction of their cytosolic domains with Vps35p". The Journal of Cell Biology. 151 (2): 297–310. doi:10.1083/jcb.151.2.297. PMC   2192648 . PMID   11038177.
  21. ↑ Rojas R, van Vlijmen T, Mardones GA, Prabhu Y, Rojas AL, Mohammed S, et al. (November 2008). "Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7". The Journal of Cell Biology. 183 (3): 513–526. doi:10.1083/jcb.200804048. PMC   2575791 . PMID   18981234.
  22. ↑ McGough IJ, Cullen PJ (August 2011). "Recent advances in retromer biology". Traffic. 12 (8): 963–971. doi: 10.1111/j.1600-0854.2011.01201.x . PMID   21463457. S2CID   22729583.
  23. ↑ Shimada A, Niwa H, Tsujita K, Suetsugu S, Nitta K, Hanawa-Suetsugu K, et al. (May 2007). "Curved EFC/F-BAR-domain dimers are joined end to end into a filament for membrane invagination in endocytosis". Cell. 129 (4): 761–772. doi: 10.1016/j.cell.2007.03.040 . PMID   17512409.
  24. ↑ Bhatia VK, Madsen KL, Bolinger PY, Kunding A, Hedegård P, Gether U, et al. (November 2009). "Amphipathic motifs in BAR domains are essential for membrane curvature sensing". The EMBO Journal. 28 (21): 3303–3314. doi:10.1038/emboj.2009.261. PMC   2776096 . PMID   19816406.
  25. ↑ Walseng E, Bakke O, Roche PA (May 2008). "Major histocompatibility complex class II-peptide complexes internalize using a clathrin- and dynamin-independent endocytosis pathway". The Journal of Biological Chemistry. 283 (21): 14717–14727. doi: 10.1074/jbc.M801070200 . PMC   2386912 . PMID   18378669.
  26. ↑ Small SA, Simoes-Spassov S, Mayeux R, Petsko GA (October 2017). "Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer's Disease". Trends in Neurosciences. 40 (10): 592–602. doi:10.1016/j.tins.2017.08.003. PMC   5654621 . PMID   28962801.
  27. ↑ Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA (July 2000). "Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations". The American Journal of Pathology. 157 (1): 277–286. doi:10.1016/s0002-9440(10)64538-5. PMC   1850219 . PMID   10880397.
  28. ↑ Simoes S, Guo J, Buitrago L, Qureshi YH, Feng X, Kothiya M, et al. (December 2021). "Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling". Cell Reports. 37 (13): 110182. doi:10.1016/j.celrep.2021.110182. PMC   8792909 . PMID   34965419.
  29. ↑ Small SA, Petsko GA (December 2020). "Endosomal recycling reconciles the Alzheimer's disease paradox". Science Translational Medicine. 12 (572): eabb1717. doi:10.1126/scitranslmed.abb1717. PMC   8025181 . PMID   33268506.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.