PROSITE documentation PDOC52072

Vacuolar protein sorting 10 protein (Vps10p) domain profile

The Vps10p domain is a large (~700 residue) luminal/extracellular domain found in type-I transmembrane receptors. It was originally found in the yeast vacuolar protein sorting 10 protein (Vps10p), which contains two copies of the domain, and it occurs in only five proteins in mammals: Sortilin, the mutually homologues SorCS1-3 and SorLA, which constitute the Vps10p receptor family and are all highly expressed in neuronal tissues. This protein family serves as a type of intracellular sorting receptor that directs hormones, lipoproteins, and signaling receptors to their correct locations within the cell to regulate cell metabolism and growth. Each family member contains a single Vps10p domain situated at the receptor N terminus. In Sortilin, which can be considered the archetypal member, the Vps10p domain makes up the entire luminal receptor, whereas additional unrelated ectodomains are found in the other four. Thus, the mutually very homologous SorCS1-3 all comprise a leucine-rich segment between the Vps10 domain and the plasma membrane, whereas SorLA contains a cluster of the ligand-binding low density lipoprotein receptor class A repeats (see <PDOC00929>), additional elements typical of the low density lipoprotein receptor family (see <PDOC51120>), and adjacent to the membrane, a domain of fibronectin type-3 repeats (see <PDOC50853>) also found in neuronal adhesion molecules. Following the ectodomains and the transmembrane segment, each receptor carries a short (50-80 amino acids) cytoplasmic domain comprising typical motifs for interaction with cytosolic adaptor molecules [1,2,3,4].

The Vps10p domain is formed by three structural units: a large N-terminal β-propeller and two cysteine-knots called 10CCa and 10CCb, which constitute the so-called 10CC (ten conserved cysteines) module (see <PDB:3WSX>). The β-propeller is composed of ten repeats (blades), forming a wheel-like structure with a funnel-shaped tunnel. Each blade is composed of a four-stranded β-sheet and is stabilized by an Asp-box repeat in the loop between strands 3 and 4. Unlike other β-propeller structures with fewer constituent blades, the Vps10p propellers have a wide, open tunnel lined by ten edge strands running parallel to the propeller axis, thus providing ample opportunity for β-sheet extension to capture extended peptides threaded into the tunnel. The C-terminal elongated 10CC module that partly wraps around the 'bottom' face of the propeller contains five conserved disulfide bridges and is a major ligand-binding region [1,3,5,6,7].

The profile we developed covers the entire Vps10p domain, including both the 10-bladed β-propeller and 10CC region.