SORT1

This gene encodes a protein that is a multi-ligand type-1 receptor with similarity to the yeast carboxypeptidase Y sorting receptor Vps10 protein. The encoded protein, a trans-Golgi network (TGN) transmembrane protein, binds a number of unrelated ligands that participate in a wide range of cellular processes; however, it lacks the typical features of a signalling receptor. In the TGN, furin mediates the activation of the mature binding form. The encoded protein consists of a large luminal domain, a single transmembrane segment and short C-terminal cytoplasmic tail. The luminal domain contains a cysteine-rich region similar to two corresponding segments in the yeast Vps10p; the cytoplasmic tail is similar to the corresponding segment of the cation-independent mannose 6-phosphate receptor and the tail also interacts with the VHS domains of GGA (Golgi-associated, gamma-adaptin homologous, ARF-interacting) proteins. [provided by RefSeq]

Full Name

sortilin 1

Function

Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface. Required for protein transport from the Golgi apparatus to the lysosomes by a pathway that is independent of the mannose-6-phosphate receptor (M6PR). Lysosomal proteins bind specifically to the receptor in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelysosomal compartment where the low pH mediates the dissociation of the complex (PubMed:16787399).
The receptor is then recycled back to the Golgi for another round of trafficking through its binding to the retromer. Also required for protein transport from the Golgi apparatus to the endosomes. Promotes neuronal apoptosis by mediating endocytosis of the proapoptotic precursor forms of BDNF (proBDNF) and NGFB (proNGFB). Also acts as a receptor for neurotensin. May promote mineralization of the extracellular matrix during osteogenic differentiation by scavenging extracellular LPL. Probably required in adipocytes for the formation of specialized storage vesicles containing the glucose transporter SLC2A4/GLUT4 (GLUT4 storage vesicles, or GSVs). These vesicles provide a stable pool of SLC2A4 and confer increased responsiveness to insulin. May also mediate transport from the endoplasmic reticulum to the Golgi.

Biological Process

Biological Process endocytosisManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process endosome to lysosome transportManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process endosome transport via multivesicular body sorting pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process extrinsic apoptotic signaling pathway via death domain receptorsManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process G protein-coupled receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process glucose importManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process Golgi to endosome transportManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process Golgi to lysosome transportManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process myotube differentiationManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process negative regulation of fat cell differentiationIEA:Ensembl
Biological Process negative regulation of lipoprotein lipase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process neuropeptide signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process neurotrophin TRK receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process ossificationIEA:UniProtKB-KW
Biological Process plasma membrane to endosome transportManual Assertion Based On ExperimentIDA:BHF-UCL
Biological Process post-Golgi vesicle-mediated transportManual Assertion Based On ExperimentIBA:GO_Central
Biological Process protein targeting to lysosomeIEA:Ensembl
Biological Process regulation of gene expressionManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process response to insulinManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process vesicle organizationManual Assertion Based On ExperimentIDA:BHF-UCL

Cellular Location

Golgi apparatus, Golgi stack membrane
Endosome membrane
Endoplasmic reticulum membrane
Nucleus membrane
Cell membrane
Lysosome membrane
Localized to membranes of the endoplasmic reticulum, endosomes, Golgi stack, lysosomes and nucleus. A small fraction of the protein is also localized to the plasma membrane. May also be found in SLC2A4/GLUT4 storage vesicles (GSVs) in adipocytes. Localization to the plasma membrane in adipocytes may be enhanced by insulin.

Involvement in disease

A common polymorphism located in a non-coding region between CELSR2 and PSRC1 alters a CEBP transcription factor binding site and is responsible for changes in hepatic expression of SORT1. Altered SORT1 expression in liver affects low density lipoprotein cholesterol levels in plasma and is associated with susceptibility to myocardial infarction.

Topology

Extracellular: 78-755
Helical: 756-778
Cytoplasmic: 779-831

PTM

The N-terminal propeptide is cleaved by furin and possibly other homologous proteases.
Palmitoylated (PubMed:18817523).
Undergoes cysteine S-palmitoylation which promotes the partitioning of the receptor into an endosomal membrane subdomain where it can interact with the retromer cargo-selective complex which mediates its retrograde trafficking to the Golgi apparatus (PubMed:18817523).
Phosphorylation at Ser-825 facilitates the interaction with GGA1.