Crystal structures of the two membrane-proximal Ig-like domains (D3D4) of LILRB1/B2: alternative models for their involvement in peptide-HLA binding

Abstract

Leukocyte immunoglobulin-like receptors (LILRs), also called CD85s, ILTs, or LIRs, are important mediators of immune activation and tolerance that contain tandem immunoglobulin (Ig)-like folds. There are 11 (in addition to two pseudogenes) LILRs in total, two with two Ig-like domains (D1D2) and the remaining nine with four Ig-like domains (D1D2D3D4). Thus far, the structural features of the D1D2 domains of LILR proteins are well defi ned, but no structures for the D3D4 domains have been reported. This is a very important fi eld to be studied as it relates to the unknown functions of the D3D4 domains, as well as their relative orientation to the D1D2 domains on the cell surface. Here, we report the crystal structures of the D3D4 domains of both LILRB1 and LILRB2. The two Iglike domains of both LILRB1-D3D4 and LILRB2-D3D4 are arranged at an acute angle (~60°) to form a bent structure, resembling the structures of natural killer inhibitory receptors. Based on these two D3D4 domain structures and previously reported D1D2/HLA I complex structures, two alternative models of full-length (four Ig-like domains) LILR molecules bound to HLA I are proposed.

Keywords

LILRs / D3D4 / HLA binding / crystal structure

References

[1] Adams, P.D., Afonine, P.V., Bunkoczi, G., Chen, V.B., Davis, I.W., Echols, N., Headd, J.J., Hung, L.W., Kapral, G.J., Grosse-Kunstleve, R.W., . (2010). PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66, 213-221 .10.1107/S0907444909052925
[2] Borges, L., Hsu, M.L., Fanger, N., Kubin, M., and Cosman, D. (1997). A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol 159, 5192-5196 .
[3] Chapman, T.L., Heikema, A.P., West, A.P., Jr., and Medzhitov, P.J. (2000). Crystal structure and ligand binding properties of the D1D2 region of the inhibitory receptor LIR-1 (ILT2). Immunity 13, 727-736 .10.1016/S1074-7613(00)00071-6
[4] Chapman, T.L., Heikeman, A.P., and Bjorkman, P.J. (1999). The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603-613 .10.1016/S1074-7613(00)80135-1
[5] Chen, Y., Chu, F., Gao, F., Zhou, B., and Gao, G.F. (2007). Stability engineering, biophysical, and biological characterization of the myeloid activating receptor immunoglobulin-like transcript 1 (ILT1/LIR- 7/LILRA2). Protein Expr Purif 56, 253-260 .10.1016/j.pep.2007.08.010
[6] Chen, Y., Gao, F., Chu, F., Peng, H., Zong, L., Liu, Y., Tien, P., and Gao, G.F. (2009). Crystal structure of myeloid cell activating receptor leukocyte Ig-like receptor A2 (LILRA2/ILT1/LIR-7) domain swapped dimer: molecular basis for its non-binding to MHC complexes. J Mol Biol 386, 841-853 .10.1016/j.jmb.2009.01.006
[7] Chen, Y., Liu, P., Gao, F., Cheng, H., Qi, J., and Gao, G.F. (2010). A dimeric structure of PD-L1: functional units or evolutionary relics? Protein Cell 1, 153-160 .
[8] Cheng, H., Mohammed, F., Nam, G., Chen, Y., Qi, J., Garner, L.I., Allen, R.L., Yan, J., Willcox, B.E., and Gao, G.F. (2011). Crystal structure of leukocyte Ig-like receptor LILRB4 (ILT3/LIR-5/CD85k): a myeloid inhibitory receptor involved in immune tolerance. J Biol Chem 286, 18013-18025 .10.1074/jbc.M111.221028
[9] Collaborative Computational Project, N. (1994). The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50, 760-763 .
[10] Colonna, M., Nakajima, H., and Cella, M. (2000). A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin Immunol 12, 121-127 .10.1006/smim.2000.0214
[11] Colonna, M., Navarro, F., Bellon, T., Llano, M., Garcia, P., Samaridis, J., Angman, L., Cella, M., and Lopez Botet, M. (1997). A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells [see comments]. J Exp Med 186, 1809-1818 .10.1084/jem.186.11.1809
[12] Cosman, D., Fanger, N., Borges, L., Kubin, M., Chin, W., Peterson, L., and Hsu, M.L. (1997). A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 7, 273-282 .10.1016/S1074-7613(00)80529-4
[13] Dietrich, J., Nakajima, H., and Colonna, M. (2000). Human inhibitory and activating Ig-like receptors which modulate the function of myeloid cells. Microbes Infect 2, 323-329 .10.1016/S1286-4579(00)00294-X
[14] Emsley, P., and Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60, 2126-2132 .10.1107/S0907444904019158
[15] Fanger, N.A., Cosman, D., Peterson, L., Braddy, S.C., Maliszewski, C.R., and Borges, L. (1998). The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. Euro J Immunol 28, 3423-3434 .10.1002/(SICI)1521-4141(199811)28:11<3423::AID-IMMU3423>3.0.CO;2-2
[16] Huang, J., Goedert, J.J., Sundberg, E.J., Cung, T.D., Burke, P.S., Martin, M.P., Preiss, L., Lifson, J., Lichterfeld, M., Carrington, M., . (2009). HLA-B*35-Px-mediated acceleration of HIV-1 infection by increased inhibitory immunoregulatory impulses. J Exp Med 206, 2959-2966 .10.1084/jem.20091386
[17] Janeway, C.A., Jr., and Medzhitov, R. (2002). Innate immune recognition. Annu Rev Immunol 20, 197-216 .10.1146/annurev.immunol.20.083001.084359
[18] Jones, D.C., Kosmoliaptsis, V., Apps, R., Lapaque, N., Smith, I., Kono, A., Chang, C., Boyle, L.H., Taylor, C.J., Trowsdale, J., . (2011). HLA class I allelic sequence and conformation regulate leukocyte Ig-like receptor binding. J Immunol 186, 2990-2997 .10.4049/jimmunol.1003078
[19] Kawai, T., and Akira, S. (2006). Innate immune recognition of viral infection. Nat Immunol 7, 131-137 .10.1038/ni1303
[20] Kim-Schulze, S., Scotto, L., Vlad, G., Piazza, F., Lin, H., Liu, Z., Cortesini, R., and Suciu-Foca, N. (2006). Recombinant Ig-like transcript 3-Fc modulates T cell responses via induction of Th anergy and differentiation of CD8+ T suppressor cells. J Immunol 176, 2790-2798 .
[21] Lanier, L.L. (2005). NK cell recognition. Annu Rev Immunol 23, 225-274 .10.1146/annurev.immunol.23.021704.115526
[22] Laskowski, R.A., Macarthur, M.W., Moss, D.S., and Thornton, J.M. (1993). Procheck- a Program to Check the Stereochemical Quality of Protein Structures. J Appl Crystallogr 26, 283-291 .10.1107/S0021889892009944
[23] Lichterfeld, M., Kavanagh, D.G., Williams, K.L., Moza, B., Mui, S.K., Miura, T., Sivamurthy, R., Allgaier, R., Pereyra, F., Trocha, A., . (2007). A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells. J Exp Med 204, 2813-2824 .10.1084/jem.20061865
[24] Lichterfeld, M., and Yu, X.G. (2012). The emerging role of leukocyte immunoglobulin-like receptors (LILRs) in HIV-1 infection. J Leukoc Biol 91, 27-33 .10.1189/jlb.0811442
[25] Maenaka, K., Juji, T., Stuart, D.I., and Jones, E.Y. (1999). Crystal structure of the human p58 killer cell inhibitory receptor (KIR2DL3) specifi c for HLA-Cw3-related MHC class I. Structure 7, 391-398 .10.1016/S0969-2126(99)80052-5
[26] Morel, E., and Bellon, T. (2008). HLA class I molecules regulate IFNgamma production induced in NK cells by target cells, viral products, or immature dendritic cells through the inhibitory receptor ILT2/CD85j. J Immunol 181, 2368-2381 .
[27] Murshudov, G.N., Vagin, A.A., and Dodson, E.J. (1997). Refi nement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 53, 240-255 .10.1107/S0907444996012255
[28] Otwinowski, Z., and Minor, W. (1997). Processing of X-ray diffraction data collected in oscillation mode. Method Enzymol 276, 307-326 .10.1016/S0076-6879(97)76066-X
[29] Prod’homme, V., Griffi n, C., Aicheler, R.J., Wang, E.C., McSharry, B.P., Rickards, C.R., Stanton, R.J., Borysiewicz, L.K., Lopez-Botet, M., Wilkinson, G.W., . (2007). The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells. J Immunol 178, 4473-4481 .
[30] Prud’homme, G.J. (2004). Altering immune tolerance therapeutically: the power of negative thinking. J Leukoc Biol 75 , 586-599 .10.1189/jlb.0803394
[31] Read, R.J. (2001). Pushing the boundaries of molecular replacement with maximum likelihood. Acta Crystallogr D Biol Crystallogr 57, 1373-1382 .10.1107/S0907444901012471
[32] Ryu, M., Chen, Y., Qi, J., Liu, J., Fan, Z., Nam, G., Shi, Y., Cheng, H., and Gao, G.F. (2011). LILRA3 binds both classical and non-classical HLA class I molecules but with reduced affi nities compared to LILRB1/LILRB2: structural evidence. PLoS One 6, e19245.
[33] Samaridis, J., and Colonna, M. (1997). Cloning of novel immunoglobulin superfamily receptors expressed on human myeloid and lymphoid cells: structural evidence for new stimulatory and inhibitory pathways. Euro J Immunol 27, 660-665 .10.1002/eji.1830270313
[34] Saverino, D., Fabbi, M., Ghiotto, F., Merlo, A., Bruno, S., Zarcone, D., Tenca, C., Tiso, M., Santoro, G., Anastasi, G., . (2000). The CD85/LIR-1/ILT2 inhibitory receptor is expressed by all human T lymphocytes and down-regulates their functions. J Immunol 165, 3742-3755 .
[35] Shiroishi, M., Kajikawa, M., Kuroki, K., Ose, T., Kohda, D., and Maenaka, K. (2006a). Crystal structure of the human monocyte-activating receptor, “Group 2” leukocyte Ig-like receptor A5 (LILRA5/LIR9/ ILT11). J Biol Chem 281, 19536-19544 .
[36] Shiroishi, M., Kuroki, K., Rasubala, L., Tsumoto, K., Kumagai, I., Kurimoto, E., Kato, K., Kohda, D., and Maenaka, K. (2006b). Structural basis for recognition of the nonclassical MHC molecule HLA-G by the leukocyte Ig-like receptor B2 (LILRB2/LIR2/ILT4/CD85d). Proc Natl Acad Sci U S A 103, 16412-16417 .
[37] Willcox, B.E., Thomas, L.M., and Bjorkman, P.J. (2003). Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nat Immunol 4, 913-919 .10.1038/ni961
[38] Willcox, B.E., Thomas, L.M., Chapman, T.L., Heikema, A.P., West, A.P., Jr., and Medzhitov, Bjorkman, P.J. (2002). Crystal structure of LIR-2 (ILT4) at 1.8 A: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18. BMC Struct Biol 2, 6.
[39] Yang, Y., Huang, J., Toth, I., Lichterfeld, M., and Yu, X.G. (2010). Mutational escape in HIV-1 CTL epitopes leads to increased binding to inhibitory myelomonocytic MHC class I receptors. PLoS One 5, e15084.
[40] Yang, Z., and Bjorkman, P.J. (2008). Structure of UL18, a peptidebinding viral MHC mimic, bound to a host inhibitory receptor. Proc Natl Acad Sci U S A 105, 10095-10100 .10.1073/pnas.0804551105
[41] Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H., Kang, X., Silvany, R., Wan, X., . (2012). Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656-660 .10.1038/nature11095