Innate immune cells are major contributors to pathogen uptake and consequently, antigen uptake and processing. Thereby these cells initiate the immune response. Many members of the C-type lectin family are expressed by these innate immune cells and primarily recognize pathogens by their glycan structures. Some of these lectins are endocytic pattern recognition receptors that, upon glycan binding trigger internalization of their cargo upon ligand binding. Hence, pathogen recognition and uptake are tightly coupled to immune cell activation and antigen processing. C-type lectin receptors recognize their carbohydrate ligands utilizing a central calcium ion coordinated by conserved amino acids in the lectin binding site. The fate of the cargo is likely determined by the kinetics and endosomal routing of the C-type lectin receptor. Endosomal calcium channels open to reduce the effective calcium concentration and additional acidification concertedly leads to cargo release. These mechanisms affect members of the C-type lectin family differently and also vary with cell type. We chose Langerin as an endocytic model receptor. This homotrimeric C-type lectin is highly expressed on epidermal Langerhans cells capturing invading pathogens such as HIV. We studied the molecular mechanisms involved in calcium binding using isothermal titration calorimetry and at atomic resolution applying protein NMR spectroscopy and molecular dynamics simulations. Biomolecular NMR provided intriguing insight into a network of amino acids involved in Ca<sup>2+</sup> recognition, while Markov state models constructed from molecular dynamics simulations led to a detailed picture of the conformational dynamics of Langerin. Together these complementary techniques indicate a potential intradomain allosteric network, while overall no interdomain allostery of the trimeric protein could be observed. We discuss these results in light of the physiological role of Langerin.

Allostery in C-type lectins

255th National Meeting (2018)

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