THE C-TYPE LECTIN LIKE FOLD IN NATURAL KILLER CELL RECEPTORS

 

Jan Dohnálek,1 Tereza Skálová,1 Petr Kolenko,1 Kristýna Kotýnková,2,3 Jindřich Hašek,1 Petr Man,2,3 Pavel Hanč,2,3 Ondřej Vaněk,2,3 Dano Rozbeský,2,3 and Karel Bezouška2,3

 

1Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Heyrovského nám. 2, 16206 Praha 6, Czech Republic,

 2Department of Biochemistry, Faculty of Science, Charles University Prague, Hlavova 8, 12840 Praha 2, Czech Republic,

3Institute of Microbiology v.v.i., Academy of Sciences of Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic,

 

Natural killer cells of the innate immune system recognize and degrade virally infected or tumour cells [1]. One significant group of NK surface receptors involved in this function are C-type lectin like (CTL) molecules involved either in activation or inhibition of the NK cell response. Receptor-ligand interactions are assumed to trigger a cascade of events in an NK cell, leading amongst others to the target cell lysis.

The mammalian receptors of the NKR-P1 family possess the extracellular part formed by a CTL domain, a neck region, a transmembrane region formed by a helix and an intracellular part responsible for signaling. The CTL fold of the extracellular domain is utilized also by the protein ligands of these receptors found on the surface of the encountered and recognized cell. In the light of some recent results predominantly protein-protein interactions are in the centre of such contacts. This implies that in the case of NK CTL receptors (or ligands) this simple fold is utilized for mediation of protein-protein contacts.

            Interestingly, the CTL fold has been observed as a basic building block of many other proteins, such as the macrophage mannose receptor, selectins, collectins and others [2]. The structure of the CTL domain is characterized by two α-helices, two small β-sheets and a long surface loop. Two or three disulfide bridges increase the stability of the structure. Even if the main characteristics of the fold remain unchanged and mostly the long loop region is involved in performing the protein’s function, several different mechanisms of exerting the functionality are employed. For some CTL proteins calcium binding in the long loop region is crucial for their affinity to ligands whereas in NK CTL receptors the same region is very likely incapable of calcium binding and at the same time involved in protein-protein interactions.

Our recent structural results suggest that the NK receptor ligands likely follow the fold, stability and dimerization pattern of the long known NK receptor human CD69 while the receptors themselves probably acquire more diverse structural arrangements [3, 4].

Interpretation of our x-ray structures of mouse NKR-P1A and Clrg, and other receptors in the context of other known CTL receptor structures, complemented by computational analysis and a critical view of results of other laboratories is expected to provide the so far most comprehensive view of structure-function features of these receptors and the specific utilization of the CTL fold in this case.

 

1. E. Vivier, E. Tomasello, M. Baratin, T. Waltzer, S. Ugolini, Nat. Immunol.  9, (2008), 503.

2. A.N. Zelensky, J.E. Gready, FEBS J. 272, (2005), 6179.

3. P. Kolenko, T. Skalova, O. Vanek, A. Stepankova, J. Duskova, J. Hasek, K. Bezouska, J. Dohnalek, Acta Crystallogr. F 65, (2009), 1258.

4. P. Kolenko, D. Rozbesky, O. Vanek, V. Kopecky, K. Hofbauerova, P. Novak, P. Pompach, J.  Hasek, T. Skalova, K. Bezouska, J. Dohnalek, J. Struct. Biol. 175, (2011), 434.

 

The authors wish to thank Uwe Müller for support at the beam line BL14.1 of Bessy II, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, and the Institute of Biotechnology ASCR for access to the X-ray diffraction suite. This work was supported by the Grant Agency of the Academy of Sciences of the Czech Republic (KJB101120805), the Czech Science Foundation (303/09/0477, 305/09/H008, 305/07/1073, P302/11/0855 and 207/10/1040), by Charles University Prague (263209/2011, 265214/2012, and project UNCE #42)), by the E.C., project SPINE2-Complexes (031220), and by the ELISA grant (226716, synchrotron access, projects 10.1.91347, 09.1.81077 and 09.2.90262).