Recombinant Mouse SorCS1 Protein, CF

SorCS1 is a type I transmembrane protein that belongs to the mammalian Vps10p (vacuolar protein-sorting 10 protein) family of receptors (1, 2). This family includes sortilin, SorLA, and three SorCS proteins. Three isoforms (SorCS1a, b and c) are known that differ only in their cytoplasmic domains (3). All three are predominantly expressed in the central nervous system, but SorCS1 can also be identified in heart, kidney and pancreatic islets (2 - 5). Although SorCS1a mediates endocytosis, only 10% of it is expressed on the cell surface. SorCS1b shows higher surface expression (45%) and is much less involved in endocytosis. SorCS1c is intermediate in expression. Mouse SorCS1a is synthesized as an 1167 amino acid (aa) preproform with a 33 aa signal sequence and a 78 aa propeptide. After proteolytic processing at a furin-type consensus sequence, the mature SorCS1a is a 1057 aa, 130 kDa protein with a 988 aa extracellular/lumenal domain (ECD). Within the ECD, mouse SorCS1 shares 93%, 98%, 91% and 98% aa identity with human, rat, bovine and canine SorCS1, respectively. It also shares 70% and 46% aa identity with the ECD of human SorCS3 and SorCS2, respectively. The ECD contains an imperfect leucine-rich repeat (LRR) plus a Vps10p domain, and binds the growth factor PDGF-BB (1, 2, 6). Expression in the hippocampus indicates that SorCS1 may modulate PDGF-BB activity in this location (6). SorCS1 has also been identified as a susceptibility gene for type 2 diabetes in overweight female mice or humans (4). Consequently, it has been proposed to affect insulin secretion by modifying PDGF-mediated growth of the islet vasculature (7). The 80 kDa ECD may be constitutively or inducibly shed, mainly via the metalloproteinase TACE/ADAM17 (6). The shed soluble form also binds PDGF. The cellular portion appears to undergo regulated intramembrane proteolysis (8).