Structural studies on ligand binding ability of Siglec-2 using molecular modeling techniques
Abstract
Siglecs are attractive therapeutic target of the major homologous subfamily of I-type lectins. The primary role of Siglecs may actually lie in the recognition and phagocytosis of bacterial pathogens that express sialic acids, maintenance of myelin organization, and inhibition of neurite outgrowth, cell-cell interactions between neurons and glial cells etc. Siglec-2, a member of the Siglec family expressed on the surface of maturing B cells and B cell lymphomas and regulates signal transduction. In this work, 3-D structure of human Siglec-2 was predicted using molecular modeling techniques. The structure of the complex in solution of Siglec-2 with ligand, 6′-Sialyl-N-acetyl lactose (6′-SialylLacNAc) was predicted using a novel docking technique. The structural analysis of the complex and calculation of theoretical dissociation constant value will help to ascertain functional roles of such sugar binding protein.
References
Angata, T. and Varki, A. (2000). Siglec-7: a sialic acid-binding lectin of the immunoglobulin super family. Glycobiology. 10: 431-438.
Angata, T., Hingorani, R., Varki, N. M. and Varki, A. (2001). Cloning and characterization of a novel mouse Siglec, mSiglec-F: differential evolution of the mouse and human (CD33) Siglec3-related gene clusters. J. Biol. Chem. 276: 45128–45136.
Aqvist, J., Medina, C. and Samuelsson, J. E. (1994). A New Method for Predicting Binding Affinity in Computer-Aided Drug Design. Protein Eng. 7: 385-391.
Aqvist, J. and Mowbray, S. L. (1995). Sugar recognition by a Glucose/Galactose receptor: Evaluation of binding energies from molecular dynamics simulations. J. Biol. Chem. 270(17): 9978-9981.
Avril, T., Floyd, H., Lopez, F., Vivier, E. and Crocker, P. R. (2004). The membraneproximal immunoreceptor tyrosinebased inhibitory motif is critical for the inhibitory signaling mediated by Siglecs7 and -9, CD33-related Siglecs expressed on human monocytes and NK cells. J. Immunol.173: 6841-6849.
Blixt, O., Collins, B. E., Van den Nieuwenhof, I. M., Crocker, P. R. and Paulson, J. C. (2003). Sialoside specificity of the Siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin associated glycoproteins. J. Biol. Chem. 278: 31007– 31019.
Brinkman-Van der Linden, E. C. and Varki, A. (2000). New aspects of siglec binding specificities, including the significance of fucosylation and of the sialyl-Tn epitope. J. Biol. Chem. 275: 8625– 8632.
Bukrinsky, J. T., Hilaire, P. M. S., Meldal, M., Crocker, P. R. and Henriksen, A. (2004). Complex of Sialoadhesin with a Glycopeptide Ligand, Biochim. Biophys. Acta. 1702: 173-179.
Collins, B. E., Blixt, O., Han, S., Duong, B., Li, H., Nathan, J. K., Bovin, N. and Paulson, J. C. (2006). High-affinity ligand probes of CD22 overcome the threshold set by cis ligands to allow for binding, endocytosis, and killing of B cells. J. Immunol. 177: 2994-3003.
Cornish, A. L., Freeman, S., Forbes, G., Zhang, J. Ni, M., Cepeda, M., Gentz, R., Augustus, M., Carter, K.C. and Crocker, P. R. (1998). Characterization of siglec-5, a novel glycoprotein expressed on myeloid cells related to CD33. Blood. 92: 2123– 2132.
Crocker, P. R. and Varki, A. (2001). Siglecs, sialic acids and innate immunity. Trends Immunol. 22: 337–342.
Crocker, P. R., Clark, E. A., Filbin, M., Gordon, S., Jones, Y. Kehrl, J. H., Kelm, S., Le Douarin. N., Powell. L., Roder. J., Schnaar. R. L., Sgroi, D. C., Stamenkovic, K., Schauer, R., Schachner, M., van den Berg, T. K., van der Merwe, P. A., Watt, S. M. and and Varki, A. (1998). Glycobiology. 8(2): v-vi.
Crocker, P. R., Vinson, M., Kelm, S. and Drickamer, K. (1999). Molecular analysis of sialoside binding to sialoadhesin by NMR and site-directed mutagenesis. Biochem. J. 341: 355–361.
Crocker, P. R., Hartnell, A., Munday, J., Nath, D. (1997). The potential role of sialoadhesin as a macrophage recognition molecule in health and disease. Glycoconj. J. 14: 601–609. Cyster, J. G., and Goodnow, C. C. (1997). Tuning antigen receptor signaling by CD22: integrating cues from antigens and the microenvironment. Immunity. 6: 509–517. Davis, I. W., Murray, L. W., Richardson, J. S. and Richardson, D. C. (2004). MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes. Nucleic Acids Research. 32: W615–W619.
Falco, M., Biassoni, R., Bottino, C., Vitale, M., Sivori, S., Augugliaro, R., Moretta, L. and Moretta, A. (1999). Identification and molecular cloning of p75/AIRM1, a novel member of the sialoadhesin family that functions as an inhibitory receptor in human natural killer cells. J. Exp. Med. 190: 793-802.
Freeman, S. D., Kelm, S., Barber, E. K. and Crocker, P. R. (1995). Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules. Blood. 85: 2005– 2012.
Ghosh, S., Bandulet, C. and Nitschke, L. (2006). Regulation of B cell development and B cell signalling by CD22 and its ligands alpha 2,6-linked sialic acids. Int Immunol. 18: 603-611.
Haas, K. M., Sen, S., Sanford, I. G., Miller, A. S., Poe, J. C. and Tedder. T. F. (2006). CD22 ligand binding regulates normal and malignant B lymphocyte survival in vivo. J. Immunol. 177: 3063-3073.
Hulte´n, J., Bonham, N. M., Nillroth, U., Hansson, T., Zuccarello, G., Bouzide, A., Aqvist, J., Classon, B., Danielson, U. H., Karle´n, A., Kvarnstro¨m, I., Samuelsson, B. and Hallberg, A. (1997). Cyclic HIV-1 Protease Inhibitors Derived from Mannitol: Synthesis, Inhibitory Potencies, and Computational Predictions of Binding Affinities. J. Med. Chem. 40: 885-897.
Ikehara, Y., Ikehara, S. K. and Paulson, J. C. (2004). Negative regulation of T cell receptor signaling by Siglec-7 (p70/AIRM) and Siglec-9. J. Biol. Chem. 279: 43117-43125.
Karlsson, K. A. (1998). Meaning and therapeutic potential of microbial recognition of host glycoconjugates. Mol. Microbiol. 29: 1–11.
Kelm, S., Schauer, R., Manuguerra, J. C., Gross, H. J. and Crocker, P. R. (1994). Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22, Glycoconj. J. 11: 576– 585.
Koradi, R., Billeter, M. and Wuthrich, K. (1996). Related Articles, MOLMOL: A program for display and analysis of macromolecular structures J. Mol. Graph. 14: 51–55.
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. Cryst. 26: 283-291.
Li, C., Tropak, M. B., Gerlai, R., Clapoff, S., Abramow-Newerly, W., Trapp, B., Peterson, A. and Roder, J. (1994). Myelination in the absence of myelinassociated glycoprotein. Nature. 369: 747-750.
Mandal, C. (1998). MODELYN – A molecular modelling program version PC-1.0 Indian Copyright No 9/98. May, A. P., Robinson, R. C., Vinson, M., Crocker, P. R. and Jones, E.Y. (1998). Crystal structure of the N-terminal domain of sialoadhesin in complex with 3' sialyllactose at 1.85Å resolution. Mol. Cell. 1: 719-728.
Meller, J. and Elber, R. (2001). Linear Optimization and a double statistical filter for protein threading protocols. Proteins, Structure, Function and Genetics. 45: 241-261.
Montag, D., Giese, K. P., Bartsch, U., Martini, R., Lang, Y., Bluthmann, H., Karthigasan, J., Kirschener, D. A., Wintergerst, E. S. and Nave, K. A. (1994). Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron. 13: 229–246.
Nicoll, G., Avril, T., Lock, K., Furukawa, K., Bovin, N. and Crocker, P. R. (2003). Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7-dependent and - independent mechanisms. Eur. J. Immunol. 33: 1642-1648.
Nicoll, G., Ni, J., Liu, D., Klenerman, P., Munday, J., Dubock, S., Mattei, M.G., Crocker, P.R. (1999). Identification and characterization of a novel siglec, siglec7, expressed by human natural killer cells and monocytes. J. Biol. Chem. 274: 34089–34095.
Powell, L. D. and Varki, A. (1994). The oligosaccharide binding specificities of CD22 beta, a sialic acid-specific lectin of B cells. J. Biol. Chem. 269: 10628– 10636.
Teodorescu, O., Galor, T., Pillardy, J. and Elber, R. (2004). Enriching the sequence substitution matrix by structural information. Proteins: Structure, Function and Bioinformatics. 54: 41-48.
Tobi, D. and Elber, R. (2000). Distance dependent, pair potential for protein folding: results from linear optimization. Proteins, Structure Function and Genetics. 41: 40-16. Varki, A. (1997). Sialic acids as ligands in recognition phenomena. FASEB J. 11: 248–255.
Varki, A. and Angata, T. (2006). Siglecs—the major subfamily of I-type lectins. Glycobiology. 16: 1R–27R. Yamaji, T., Teranishi, T., Alphey, M. S., Crocker, P. R. and Hashimoto, Y. (2002). A small region of the natural killer cell receptor, Siglec-7, is responsible for its preferred binding to α 2,8-disialyl and branched α 2,6-sialyl residues: A comparison with siglec-9. J. Biol. Chem. 277: 6324–6332.
Zaccai, N. R., Maenaka, K., Maenaka, T., Crocker, P. R., Brossmer, R., Kelm, S. and Jones, E. Y. (2003). Structure-guided design of sialic acid-based siglec inhibitors and crystallographic analysis in complex with sialoadhesin. Structure. 11: 557– 567.
