C-type lectin family
The C-type lectin family is a group of lectins that recognize carbohydrate structures in a calcium-dependent manner. Whether soluble or membrane bound, all the C-type lectin family members share a highly conserved lectin prototype, namely the carbohydrate recognition domain (CRD). The length of all CRD domains is well-conserved in all C-type lectins, which is approximately 130 amino acids. Sequence alignment of these CRDs revealed 14 invariant and 18 highly conserved residues, including at least two pairs of cysteines that contribute to the formation of intramolecular disulfide bridges. The spatial structure of the C-type lectin CRD fold originally resolved from the crystal structure of rat is typically made up of two a-helices, five (3-strands, and a calcium/sugar recognition surface with irregular loops. The CRD loop is formed by two closely arranged anti-parallel β-strands at the N- and C-termini, and the CRD region is flanked by two consecutive a-helices. The other three β- strands make up the core beneath the sugar-binding surface. The number of calcium-binding sites in the CRD domain varies among different C-type lectins (from 1 to 4). However, the second site, calcium-binding site 2 (Ca2+ 2), mediates carbohydrate recognition and thus is the most conserved and crucial one.
C-type lectin like receptors
Some lectins possess part, or the entire classical CRD domain, but fail to recognize sugar and are functionally independent of calcium ions. Drickamer defined molecules of this kind as members of the C-type lectin-like superfamily and their special CRD domains as C-type lectin-like domains (CTLD). Due to divergence, this superfamily contains many branches, with only a small portion containing conserved CRD. For example, although some NK cell lectin receptors have a CRD domain, like the NKG2 family, they recognize proteins such as MHC molecules, instead of sugars. Such features were also seen in antifreeze proteins and lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1), which were the receptors for ice and lipids, respectively. Some molecules display neither similar sequences nor binding features to CRD members. However, the spatial structure of these molecules showed a folding format close to that found in classical C-type lectins. It is believed that convergence contributed to this topological similarity, yet evidence is still lacking.
C-type lectin classification
C-type lectins can be classified upon several different criteria. However, based on protein structure and domain organization or sequence homology, the same seven groups were defined.
Group I includes three proto-glycans, which are present in the extracellular matrix. Group II represents type II endocytic receptors, with a short N- terminal cytoplasmic tail containing a signal sequence, and C-terminal CRD domain. Mammalian asialoglycoprotein receptor, chicken hepatic lectin and lymphocyte receptors belong to this group. Group III molecules are called collectins, comprised of collagenous N-terminal region and a C-terminal CRD domain in one polypeptide. Collectins are soluble molecules, arranged in the form of homo-oligomers. Examples in this group include mannose binding proteins (MBP) and pulmonary surfactant apo-proteins, which function in humoral defense. Group IV was composed of selectin molecules. Three types of selectins were identified so far, all bearing a CRD domain at the N-terminal end, an epidermal growth factor-like domain, various numbers of complement-binding repeats at the stalk region, and a short cytoplasmic tail. Selectins recognize endogenous sugar structures and mediate the adhesion between leukocytes and endothelia.
Natural killer cell receptors constitute Group V C-type lectins. The molecules in this group are typically comprised of one CRD domain at the C-terminal end, a neck region, transmembrane domain, and a cytoplasmic domain with a signaling motif. Some receptors form hetero or homo-dimers through a disulfide bond at the neck region. The functions of these NK cell receptors involve distinguishing self or non-self ligands, and eliciting consequent activating or inhibitory signals. The endocytic receptors including macrophage mannose receptor, PLA2 receptor, DEC-205 and Endo 180 were identified as group VI, because they are type I transmembrane receptors. Members in this group bear multiple, usually 8-10, CRD domains at their N-terminus. Group VII molecules are distinct in that they only have a single CRD domain, with no other accessory regions. Molecules in this group are present more widely in invertebrates and lower vertebrates. In humans, only two pancreas-related group VII molecules were isolated so far, with unknown ligands and functions.