Retromer is a complex of

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s that has been shown to be important in recycling transmembrane receptors from

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...

s 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. Retromer is a heteropentameric complex, which in humans is composed of a less defined membrane-associated sorting nexin dimer ( SNX1,

SNX2 Sorting nexin-2 is a protein that in humans is encoded by the ''SNX2'' gene. Function This gene encodes a member of the sorting nexin family. Members of this family contain a PX domain, phox (PX) domain, which is a phosphoinositide binding dom ...

, 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 including M6PR, wntless, SORL1 (which is also a receptor for other cargo proteins such as APP), and sortilin. 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. Age-related loss of OXR1 causes retromer decline.

Structure

The retromer complex is highly conserved:

homologs Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same loci, where they provide points along each chromosome th ...

have been found in '' C. elegans'',

mouse A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus'' ...

and

human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

. The retromer complex consists of 5 proteins in yeast: Vps35p, Vps26p, Vps29p, Vps17p, Vps5p. The mammalian retromer consists of Vps26, Vps29, Vps35, SNX1 and

, and possibly SNX5 and SNX6. 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.

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. 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. 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 Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and late-onset Parkinson disease Retromer also seems to play a role in

Hepatitis C Virus The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family ''Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer ( hepatoc ...

replication.

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. The nucleation complex is formed through the interaction of VPS complex with GTP-activated

Rab7 Ras-related protein Rab-7a is a protein that in humans is encoded by the ''RAB7A'' gene. Ras-related protein Rab-7a is involved in endocytosis, which is a process that brings substances into a cell. The process of endocytosis works by folding the ...

with

clathrin Clathrin is a protein that plays a role in the formation of coated vesicles. Clathrin was first isolated by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskel ...

, clathrin-adaptors and various binding proteins. 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. Once the cargo carriers are matured, the carrier scission is then catalyzed by dynamin-II or EHD1, 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 Dyneins are a family of cytoskeletal motor proteins (though they are actually protein complexes) that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargo ...

. 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. Dysfunction of this branch of the retromer recycling pathway causes endosomal protein traffic jams that are linked to Alzheimer’s disease. 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”.

References