Langerin : a specific CLR of Langerhans cells
As DC-SIGN, langerin is a type II C-type lectin, almost exclusively expressed on epidermal LCs, but also present on dermal CD103+ DCs and lymph node resident CD8+ DCs Valladeau, J, Ravel, O, Dezutter-Dambuyant, C, et al., (2000), Romani, N, Clausen, B. E, & Stoitzner, P. (2010), doyaga, J, Suda, N, Suda, K, et al., (2009). LCs is a subset of DCs, whose role is not completely clear. Although initially they were assumed to function as APCs, like dermal or stromal DCs Hunger, R. E, Sieling, P. A, Ochoa, M. T, et al., (2004), the accumulating evidence of their fail to present antigens from various viruses and parasites to T cells activation and the observation that LCs induce T regulatory cells supports the presumption that these cells may have an immunosuppressive, tolerogenic role Stoitzner, P & Romani, N. (2011).
A characteristic hallmark of LCs is the Birbeck granules (fig.16), and langerin has been shown to be the main component and responsible for the formation of these tennis racquet or
rod-shaped membranous structures Valladeau, J, Ravel, O, Dezutter-Dambuyant, C et al., (2000), Cunningham, A. L, Carbone, F, & Geijtenbeek, T. B. H. (2008), de Jong, M. A. W. P, Vriend, L. E. M, Theelen, B, et al., (2010)>. It binds pathogens through the recognition of high-mannose structures Stambach, N. S & Taylor, M. E. (2003) present on viral envelopes, mannan and β−glucan structures on fungi de Jong, M. A. W. P, Vriend, L. E. M, Theelen, B, et al., (2010).
As already described in sub-subsection 188.8.131.52, langerin is particularly important in protection against HIV infection since it captures HIV-1 virions by binding to envelope glycoprotein gp120, and this leads to their degradation in BGs de Witte, L, Nabatov, A, Pion, M, et al., (2007). The anti-fungal function of LCs is suggested as well, with a central protective role exerted also by langerin de Jong, M. A. W. P, Vriend, L. E. M, Theelen, B, et al., (2010).
4.1. The structure and carbohydrate recognition by langerin
Langerin is a type II transmembrane receptor (328 amino acids, 37.5 kDa) with an overall molecular organization similar to DC-SIGN and other CLRs : it consists of N-terminal cytoplasmic domain, transmembrane domain, neck region, and a C-terminal C-type CRD (fig. 17) Valladeau, J, Ravel, O, Dezutter-Dambuyant, C, et al., (2000). The cytoplasmic domain of langerin contains a proline-rich signaling motif (WPREPPP), which could function as a docking site for signal transduction proteins, and indeed, it was demonstrated to be important for langerin intracellular targeting Thépaut, M, Valladeau, J, Nurisso, A, et al., (2009). Nonetheless, the role of langerin signaling is still obscure van den Berg, L. M, Gringhuis, S. I, & Geijtenbeek, T. B. H. (2012).
The CRD of langerin (fig 18) contains EPN motif indicating its specificity for mannose type sugars. A glycan array analysis using truncated trimeric langerin, has revealed several types of carbohydrates as ligands of langerin Feinberg, H, Powlesland, A. S, Taylor, M. E, & Weis, W. I. (2010). As expected, langerin bound high-mannose N-linked oligosaccharides, however, the only fucose-based ligand of langerin was blood group B antigen (Gal α1–3 (Fuc α1–2) Gal). Moreover, a peculiar property of langerin to bind glycans terminating in 6-sulfated galactose was also found Feinberg, H, Powlesland, A. S, Taylor, M. E, & Weis, W. I. (2010) that explained the ability of langerin to recognize keratin sulphate Tateno, H, Ohnishi, K, Yabe, R, et al., (2010).
Structural studies of ligand recognition by langerin revealed that it binds high-mannose structures through non-reducing terminal mannoses and internal Man α1-2 Man (fig. 19A), which has multiple binding modes in the conventional Ca2+-dependent sugar-binding site. The binding mode of this non-reducing mannose residue is virtually the same as mannose monosaccharide (pdb:3P7G), except that it is 180° flipped by the axis perpendicular to C3-C4 bond. In contrast to DC-SIGN, langerin has only a small extended binding site that contacts other sugar residues in high-mannose oligosaccharides, and better binding affinity to these oligosaccharides compared to mannose may be a statistical effect of having multiple available mannose residues, as is in case of DC-SIGN Feinberg, H, Taylor, M. E, Razi, N, et al., (2011).
It was also demonstrated that langerin is unique among C-type CRDs since apart of binding mannose/fucose type sugars, it is also able to interact with galactose-based saccharides : it recognizes 6SO4–Gal residues that are present in keratan sulfate as 6SO4–Galb1–4GlcNAc repeating unit Tateno, H, Ohnishi, K, Yabe, R, et al., (2010). In crystal structure of langerin CRD in complex with 6SO4–Galb1–4GlcNAc (fig. 19B) the galactose residue was found to make coordination to Ca2+ by axial 4-OH and equatorial 3-OH groups, and the galactose residue packs against Ala289. Finally, the SO4 group makes salt bridges with Lys299 and Lys313 Feinberg, H, Taylor, M. E, Razi, N, et al., (2011).
Trimeric structure of langerin and its role in BG formation
The neck region of langerin is composed of the series of heptads (fig. 17), although these repeats are not as obvious as the tandem 23 amino acid repeats in the neck of DC-SIGN. These heptads are responsible for the oligomerization of langerin into trimers (fig. 20A) Stambach, N. S & Taylor, M. E. (2003), Feinberg, H, Powlesland, A. S, Taylor, M. E, & Weis, W. I. (2010).
The trimeric langerin is rather a rigid unit with the CRDs in fixed positions as can be seen in the crystal structure of the truncated trimeric langerin : the CRDs make multiple contacts with the neck region and this leads to the arrangement of primary sugar-binding sites at fixed positions separated by a distance of 42Å (fig. 20B). The only significant flexibility in the CRD was observed at the loop region comprising residues 258-262 (fig. 18), and results most likely due to the absence of auxiliary Ca2+ sites that are present in many other CRDs. This kind of fixed organization of sugar-binding sites may restrict ligand recognition by langerin Feinberg, H, Powlesland, A. S, Taylor, M. E, & Weis, W. I. (2010).