PROSITE documentation PDOC00537

C-type lectin domain signature and profile

A number of different families of proteins share a conserved domain which was first characterized in some animal lectins and which seem to function as a calcium-dependent carbohydrate-recognition domain [1,2,3]. This domain, which is known as the C-type lectin domain (CTL) or as the carbohydrate-recognition domain (CRD), consists of about 110 to 130 residues. There are four cysteines which are perfectly conserved and involved in two disulfide bonds. A schematic representation of the CTL domain is shown below.

                                                         +------+
                                                         |      |
     xcxxxxcxxxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxCxxxxWxCxxxxCx
      |    |       |                                     ************|*
      +----+       +-------------------------------------------------+

'C': conserved cysteine involved in a disulfide bond.
'c': optional cysteine involved in a disulfide bond.
'*': position of the pattern.

The categories of proteins, in which the CTL domain has been found, are listed below.

Type-II membrane proteins where the CTL domain is located at the C-terminal extremity of the proteins:

• Asialoglycoprotein receptors (ASGPR) (also known as hepatic lectins) [4]. The ASGPR's mediate the endocytosis of plasma glycoproteins to which the terminal sialic acid residue in their carbohydrate moieties has been removed.
• Low affinity immunoglobulin epsilon Fc receptor (lymphocyte IgE receptor), which plays an essential role in the regulation of IgE production and in the differentiation of B cells.
• Kupffer cell receptor. A receptor with an affinity for galactose and fucose, that could be involved in endocytosis.
• A number of proteins expressed on the surface of natural killer T-cells: NKG2, NKR-P1, YE1/88 (Ly-49), CD69 and on B-cells: CD72, LyB-2. The CTL- domain in these proteins is distantly related to other CTL-domains; it is unclear whether they are likely to bind carbohydrates.

Proteins that consist of an N-terminal collagenous domain followed by a CTL-domain [5], these proteins are sometimes called 'collectins':

• Pulmonary surfactant-associated protein A (SP-A). SP-A is a calcium- dependent protein that binds to surfactant phospholipids and contributes to lower the surface tension at the air-liquid interface in the alveoli of the mammalian lung.
• Pulmonary surfactant-associated protein D (SP-D).
• Conglutinin, a calcium-dependent lectin-like protein which binds to a yeast cell wall extract and to immune complexes through the complement component (iC3b).
• Mannan-binding proteins (MBP) (also known as mannose-binding proteins). MBP's bind mannose and N-acetyl-D-glucosamine in a calcium-dependent manner.
• Bovine collectin-43 (CL-43).

Selectins (or LEC-CAM) [6,7]. Selectins are cell adhesion molecules implicated in the interaction of leukocytes with platelets or vascular endothelium. Structurally, selectins consist of a long extracellular domain, followed by a transmembrane region and a short cytoplasmic domain. The extracellular domain is itself composed of a CTL-domain, followed by an EGF-like domain and a variable number of SCR/Sushi repeats. Known selectins are:

• Lymph node homing receptor (also known as L-selectin, leukocyte adhesion molecule-1, (LAM-1), leu-8, gp90-mel, or LECAM-1)
• Endothelial leukocyte adhesion molecule 1 (ELAM-1, E-selectin or LECAM-2). The ligand recognized by ELAM-1 is sialyl-Lewis x.
• Granule membrane protein 140 (GMP-140, P-selectin, PADGEM, CD62, or LECAM- 3). The ligand recognized by GMP-140 is Lewis x.

Large proteoglycans that contain a CTL-domain followed by one copy of a SCR/ Sushi repeat, in their C-terminal section:

• Aggrecan (cartilage-specific proteoglycan core protein). This proteoglycan is a major component of the extracellular matrix of cartilagenous tissues where it has a role in the resistance to compression.
• Brevican.
• Neurocan.
• Versican (large fibroblast proteoglycan), a large chondroitin sulfate proteoglycan that may play a role in intercellular signalling.

In addition to the CTL and Sushi domains, these proteins also contain, in their N-terminal domain, an Ig-like V-type region, two or four link domains (see <PDOC00955>) and up to two EGF-like repeats.

Two type-I membrane proteins:

• Mannose receptor from macrophages. This protein mediates the endocytosis of glycoproteins by macrophages in several recognition and uptake processes. Its extracellular section consists of a fibronectin type II domain followed by eight tandem repeats of the CTL domain.
• 180 Kd secretory phospholipase A2 receptor (PLA2-R). A protein whose structure is highly similar to that of the mannose receptor.
• DEC-205 receptor. This protein is used by dendritic cells and thymic epithelial cells to capture and endocytose diverse carbohydrate-binding antigens and direct them to antigen-processing cellular compartiments. DEC- 205 extracellular section consists of a fibronectin type II domain followed by ten tandem repeats of the CTL domain.
• Silk moth hemocytin, an humoral lectin which is involved in a self-defence mechanism. It is composed of 2 FA58C domains (see <PDOC00988>), a CTL domain, 2 VWFC domains (see <PDOC00928), and a CTCK (see <PDOC00912>).

Various other proteins that uniquely consist of a CTL domain:

• Invertebrate soluble galactose-binding lectins. A category to which belong a humoral lectin from a flesh fly; echinoidin, a lectin from the coelomic fluid of a sea urchin; BRA-2 and BRA-3, two lectins from the coelomic fluid of a barnacle, a lectin from the tunicate Polyandrocarpa misakiensis and a newt oviduct lectin. The physiological importance of these lectins is not yet known but they may play an important role in defense mechanisms.
• Pancreatic stone protein (PSP) (also known as pancreatic thread protein (PTP), or reg), a protein that might act as an inhibitor of spontaneous calcium carbonate precipitation.
• Pancreatitis associated protein (PAP), a protein that might be involved in the control of bacterial proliferation.
• Tetranectin, a plasma protein that binds to plasminogen and to isolated kringle 4.
• Eosinophil granule major basic protein (MBP), a cytotoxic protein.
• A galactose specific lectin from a rattlesnake.
• Two subunits of a coagulation factor IX/factor X-binding protein (IX/X-bp), a snake venom anticoagulant protein which binds with factors IX and X in the presence of calcium.
• Two subunits of a phospholipase A2 inhibitor from the plasma of a snake (PLI-A and PLI-B).
• A lipopolysaccharide-binding protein (LPS-BP) from the hemolymph of a cockroach [8].
• Sea raven antifreeze protein (AFP) [9].

As a signature pattern for this domain, we selected the C-terminal region with its three conserved cysteines.