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Abstract: proteasomes are responsible for the production of the majority of cytotoxic T lymphocyte (CTL) epitopes. Hence, it is important to identify correctly which peptides will be generated by proteasomes from an unknown protein. However, the pool of proteasome cleavage data used in the prediction algorithms, whether from major histocompatibility complex (MHC) I ligand or in vitro digestion data, is not identical to in vivo proteasomal digestion products. Therefore, the accuracy and reliability of these models still need to be improved. In this paper, three types of proteasomal cleavage data, constitutive proteasome (cCP), immunoproteasome (iCP) in vitro cleavage, and MHC I ligand data, were used for training cleave-site predictive methods based on the kernel-function stabilized matrix method (KSMM). The predictive accuracies of the KSMM+pair coefficients were 75.0%, 72.3%, and 83.1% for cCP, iCP, and MHC I ligand data, respectively, which were comparable to the results from support vector machine (SVM). The three proteasomal cleavage methods were combined in turn with MHC I-peptide binding predictions to model MHC I-peptide processing and the presentation pathway. These integrations markedly improved MHC I peptide identification, increasing area under the receiver operator characteristics (ROC) curve (AUC) values from 0.82 to 0.91. The results suggested that both MHC I ligand and proteasomal in vitro degradation data can give an exact simulation of in vivo processed digestion. The information extracted from cCP and iCP in vitro cleavage data demonstrated that both cCP and iCP are selective in their usage of peptide bonds for cleavage.

[1]Alvarez, I., Sesma, L., Marcilla, M., Ramos, M., Marti, M., Camafeita, E., de Castro, J.A., 2001. Identification of novel HLA-B27 ligands derived from polymorphic regions of its own or other class I molecules based on direct generation by 20S proteasome. J. Biol. Chem., 276(35):32729-32737.

[2]Bairoch, A., Apweiler, R., 2000. The SWISS-PROT protein sequence database and its supplement TrEMBL in 2000. Nucleic Acids Res., 28(1):45-48.

[3]Beekman, N.J., van Veelen, P.A., van Hall, T., Neisig, A., Sijts, A., Camps, M., Kloetzel, P.M., Neefjes, J.J., Melief, C.J., Ossendorp, F., 2000. Abrogation of CTL epitope processing by single amino acid substitution flanking the C-terminal proteasome cleavage site. J. Immunol., 164(4):1898-1905.

[4]Bhasin, M., Raghava, G.P.S., 2005. Pcleavage: an SVM based method for prediction of constitutive proteasome and immunoproteasome cleavage sites in antigenic sequences. Nucleic Acids, 33(s2):W202-W207.

[5]Bhasin, M., Singh, H., Raghava, G.P.S., 2003. MHCBN: a comprehensive database of MHC binding and non-binding peptides. Bioinformatics, 19(5):665-666.

[6]Blythe, M.J., Doytchinova, I.A., Flower, D.R., 2002. JenPep: a database of quantitative functional peptide data for immunology. Bioinformatics, 18(3):434-439.

[7]Cascio, P., Hilton, C., Kisselev, A.F., Rock, K.L., Goldberg, A.L., 2001. 26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide. EMBO J., 20(10):2357-2366.

[8]Chang, C.C., Lin, C.J., 2011. LIBSVM: a library for support vector machines. ACM Trans. Intell. Syst. Technol., 2(3):27.

[9]Chapiro, J., Claverol, S., Piette, F., Ma, W., Stroobant, V., Guillaume, B., Gairin, J.E., Morel, S., Burlet-Schiltz, O., Monsarrat, B., et al., 2006. Destructive cleavage of antigenic peptides either by the immunoproteasome or by the standard proteasome results in differential antigen presentation. J. Immunol., 176(2):1053-1061.

[10]Coux, O., Tanaka, K., Goldberg, A.L., 1996. Structure and functions of the 20S and 26S proteasomes. Ann. Rev. Biochem., 65:801-847.

[11]Dick, L.R., Aldrich, C., Jameson, S.C., Moomaw, C.R., Pramanik, B.C., Doyle, C.K., DeMartino, G.N., Bevan, M.J., Forman, J.M., Slaughter, C.A., 1994. Proteolytic processing of ovalbumin and beta-galactosidase by the proteasome to a yield antigenic peptides. J. Immunol., 152(8):3884-3894.

[12]Dick, T.P., Nussbaum, A.K., Deeg, M., Heinemeyer, W., Groll, M., Schirle, M., Keilholz, W., Stevanovic, S., Wolf, D.H., Huber, R., et al., 1998. Contribution of proteasomal beta-subunits to the cleavage of peptide substrates analyzed with yeast mutants. J. Biol. Chem., 273(40):25637-25646.

[13]Diez-Rivero, C.M., Lafuente, E.M., Reche, P.A., 2010. Computational analysis and modeling of cleavage by the immunoproteasome and the constitutive proteasome. BMC Bioinf., 11(1):479.

[14]Ehring, B., Meyer, T.H., Eckerskorn, C., Lottspeich, F., Tampé, R., 1996. Effects of major-histocompatibility-complex-encoded subunits on the peptidase and proteolytic activities of human 20S proteasomes. Cleavage of proteins and antigenic peptides. Eur. J. Biochem., 235(1-2):404-415.

[15]Emmerich, N.P.N., Nussbaum, A.K., Stevanovic, S., Priemer, M., Toes, R.E.M., Rammensee, H.G., 2000. The human 26S and 20S proteasomes generate overlapping but different sets of peptide fragments from a model protein substrate. J. Biol. Chem., 275(28):21140-21148.

[16]Ginodi, I., Vider-Shalit, T., Tsaban, L., Louzoun, Y., 2008. Precise score for the prediction of peptides cleaved by the proteasome. Bioinformatics, 24(4):477-483.

[17]Goldberg, A.L., Cascio, P., Saric, T., Rock, K.L., 2002. The importance of the proteasome and subsequent proteolytic steps in the generation of antigenic peptides. Mol. Immunol., 39:147-164.

[18]Goldobin, D.S., Zaikin, A., 2009. Towards quantitative prediction of proteasomal digestion patterns of proteins. J. Stat. Mech., 2009:P01009.

[19]Heinemeyer, W., Ramos, P.C., Dohmen, R.J., 2004. The ultimate nanoscale mincer: assembly, structure and active sites of the 20S proteasome core. Cell Mol. Life Sci., 61(13):1562-1578.

[20]Holzhütter, H.G., Kloetzel, P.M., 2000. A kinetic model of vertebrate 20S proteasome accounting for the generation of major proteolytic fragments from oligomeric peptide substrates. Biophys. J., 79(3):1196-1205.

[21]Huber, E.M., Basler, M., Schwab, R., Heinemeyer, W., Kirk, C.J., Groettrup, M., Groll, M., 2012. Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell, 148(4):727-738.

[22]Jacob, L., Vert, J.P., 2008. Efficient peptide-MHC-I binding prediction for alleles with few known binders. Bioinformatics, 24(3):358-366.

[23]Keşmir, C., Nussbaum, A.K., Schild, H., Detours, V., Brunak, S., 2002. Prediction of proteasome cleavage motifs by neural networks. Prot. Eng., 15(4):287-296.

[24]Keşmir, C., van Noort, V., de Boer, R.J., Hogeweg, P., 2003. Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome. Immunogenetics, 55(7):437-449.

[25]Kosmrlj, A., Read, E.L., Qi, Y., Allen, T.M., Altfeld, M., Deeks, S.G., Pereyra, F., Carrington, M., Walker, B.D., Chakraborty, A.K., 2010. Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature, 465(7296):350-354.

[26]Leibovitz, D., Koch, Y., Pitzer, F., Fridkin, M., Dantes, A., Baumeister, W., Amsterdam, A., 1994. Sequential degradation of the neuropeptide gonadotropin-releasing hormone by the 20 S granulosa cell proteasomes. FEBS Lett., 346(2-3):203-206.

[27]Liu, T., Liu, W., Song, Z., Jiao, C.B., Zhu, M.H., Wang, X.G., 2009. Computational prediction of the specificities of proteasome interaction with antigen protein. Cell Mol. Immunol., 6(2):135-142.

[28]Lucchiari-Hartz, M., Lindo, V., Hitziger, N., Gaedicke, S., Saveanu, L., Endert, P.M., 2003. Differential proteasomal processing of hydrophobic and hydrophilic protein regions: contribution to cytotoxic T lymphocyte epitope clustering in HIV-1-Nef. PNAS, 100(13):7755-7760.

[29]Ma, W.B., Vigneron, N., Chapiro, J., Stroobant, V., Germeau, C., Boon, T., Coulie, P.G., van den Eynde, B.J., 2011. A MAGE-C2 antigenic peptide processed by the immunoproteasome is recognized by cytolytic T cells isolated from a melanoma patient after successful immunotherapy. Int. J. Cancer, 129(10):2427-2434.

[30]Metropolis, N., Ulam, S., 1949. The Monte Carlo method. J. Am. Stat. Assoc., 44(247):335-341.

[31]Mommaas, B., Kamp, J., Drijfhout, J.W., Beekman, N., Ossendorp, F., van Veelen, P., den Haan, J., Goulmy, E., Mutis, T., 2002. Identification of a novel HLA-B60-restricted T cell epitope of the minor histocompatibility antigen HA-1 locus. J. Immunol., 169(6):3131-3136.

[32]Morel, S., Lévy, F., Burlet-Schiltz, O., Brasseur, F., Probst-Kepper, M., Peitrequin, A.L., Monsarrat, B., van Velthoven, R., Cerottini, J.C., Boon, T., et al., 2000. Processing of some antigens by the standard proteasome but not by the immunoproteasome results in poor presentation by dendritic cells. Immunity, 12(1):107-117.

[33]Muchamuel, T., Basler, M., Aujay, M.A., Suzuki, E., Kalim, K.W., Lauer, C., Sylvain, C., Ring, E.R., Shields, J., Jiang, J., et al., 2009. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med., 15(7):781-787.

[34]Niedermann, G., Butz, S., Ihlenfeldt, H.G., Grimm, R., Lucchiari, M., Hoschützky, H., Jung, G., Maier, B., Eichmann, K., 1995. Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules. Immunity, 2(3):289-299.

[35]Niedermann, G., King, G., Butz, S., Birsner, U., Grimm, R., Shabanowitz, J., Hunt, D.F., Eichmann, K., 1996. The proteolytic fragments generated by vertebrate proteasomes: structural relationships to major histocompatibility complex class I binding peptides. PNAS, 93(16):8572-8577.

[36]Niedermann, G., Grimm, R., Geier, E., Maurer, M., Realini, C., Gartmann, C., Soll, J., Omura, S., Rechsteiner, M.C., Baumeister, W., et al., 1997. Potential immunocompetence of proteolytic fragments produced by proteasomes before evolution of the vertebrate immune system. J. Exp. Med., 186(2):209-220.

[37]Nielsen, M., Lundegaard, C., Lund, O., 2007. Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method. BMC Bioinf., 8(1):238.

[38]Nussbaum, A.K., Dick, T.P., Keilholz, W., 1998. Cleavage motifs of the yeast 20S proteasome b subunits deduced from digests of enolase 1. PNAS, 95(21):12504-12509.

[39]Nussbaum, A.K., Kuttler, C., Hadeler, K.P., Rammensee, H.G., Schild, H., 2001. PAProC: a prediction algorithm for proteasomal cleavages available on the WWW. Immunogenetics, 53(2):87-94.

[40]Ossendorp, F., Neisig, A., Ruppert, T., Groettrup, M., Sijts, A., Mengedë, E., Kloetzel, P.M., Neefjes, J., Koszinowski, U., Melief, C., 1996. A single residue exchange within a viral ctl epitope alters proteasome-mediated degradation resulting in lack of antigen presentation. Immunity, 5(2):115-124.

[41]Peters, B., Sette, A., 2005. Generating quantitative models describing the sequence specificity of biological processes with the stabilized matrix method. BMC Bioinf., 6(1):132.

[42]Peters, B., Janek, K., Kuckelkorn, U., Holzhütter, H.G., 2002. Assessment of proteasomal cleavage probabilities from kinetic analysis of time-dependent product formation. J. Mol. Biol., 318(3):847-862.

[43]Peters, B., Tong, W., Sidney, J., Sette, A., Weng, Z., 2003. Examining the independent binding assumption for binding of peptide epitopes to MHC-I molecules. Bioinformatics, 19(14):1765-1772.

[44]Rivett, A.J., 1985. Purification of a liver alkaline protease which degrades oxidatively modified glutamine synthetase. Characterization as a high molecular weight cysteine proteinase. J. Biol. Chem., 260(23):12600-12606.

[45]Sandberg, M., Eriksson, L., Jonsson, J., Sjöström, M., Wold, S., 1998. New chemical descriptors relevant for the design of biologically active peptides. A multivariate characterization of 87 amino acids. J. Med. Chem., 41(14):2481-2491.

[46]Saxová, P., Buus, S., Brunak, S., Keşmir, C., 2003. Predicting proteasomal cleavage sites: a comparison of available methods. Int. Immunol., 15(7):781-787.

[47]Schultz, E.S., Chapiro, J., Lurquin, C., Claverol, S., Burlet-Schiltz, O., Warnier, G., Russo, V., Morel, S., Levy, F., Boon, T., et al., 2002. The production of a new MAGE-3 peptide presented to cytolytic T lymphocytes by HLA-B40 requires the immunoproteasome. J. Exp. Med., 195(4):391-399.

[48]Seifert, U., Bialy, L.P., Ebstein, F., Bech-Otschir, D., Voigt, A., Schröter, F., Prozorovski, T., Lange, N., Steffen, J., Rieger, M., et al., 2010. Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell, 142(4):613-624.

[49]Shimbara, N., Nakajima, H., Tanahashi, N., Ogawa, K., Niwa, S., Uenaka, A., Nakayama, E., Tanaka, K., 1997. Double-cleavage production of the CTL epitope by proteasomes and PA28: role of the flanking region. Genes Cells, 2(12):785-800.

[50]Sorokin, A.V., Kim, E.R., Ovchinnikov, L.P., 2009. Proteasome system of protein degradation and processing. Biochemistry, 74(13):1411-1442.

[51]Sun, Y., Sijts, A.J., Song, M., Janek, K., Nussbaum, A.K., Kral, S., Schirle, M., Stevanovic, S., Paschen, A., Schild, H., et al., 2002. Expression of the proteasome activator PA28 rescues the presentation of a cytotoxic T lymphocyte epitope on melanoma cells. Cancer Res., 62(10):2875-2882.

[52]Swets, J.A., 1988. Measuring the accuracy of diagnostic systems. Science, 240(4857):1285-1293.

[53]Tenzer, S., Stoltze, L., Schonfisch, B., Dengjel, J., Muller, M., Stevanovic, S., 2004. Quantitative analysis of prion protein degradation by constitutive and immuno-20S proteasomes indicates differences correlated with disease susceptibility. J. Immunol., 172(2):1083-1091.

[54]Tenzer, S., Peters, B., Bulik, S., Schoor, O., Lemmel, C., Schatz, M.M., Kloetzel, P.M., Rammensee, H.G., Schild, H., Holzhütter, H.G., 2005. Modeling the MHC class I pathway by combining predictions of proteasomal cleavage, TAP transport and MHC class I binding. Cell Mol. Life Sci., 62(9):1025-1037.

[55]Toes, R.E., Nussbaum, A.K., Degermann, S., Schirle, M., Emmerich, N.P., 2001. Discrete cleavage motifs of constitutive and immunoproteasomes revealed by quantitative analysis of cleavage products. J. Exp. Med., 194(1):1-12.

[56]Vigneron, N., Stroobant, V., Chapiro, J., Ooms, A., Degiovanni, G., Morel, S., van der Bruggen, P., Boon, T., van den Eynde, B.J., 2004. An antigenic peptide produced by peptide splicing in the proteasome. Science, 304(5670):587-590.

[57]Warren, E.H., Vigneron, N.J., Gavin, M.A., Coulie, P.G., Stroobant, V., Dalet, A., Tykodi, S.S., Xuereb, S.M., Mito, J.K., Riddell, S.R., et al., 2006. An antigen produced by splicing of noncontiguous peptides in the reverse order. Science, 313(5792):1444-1447.

[58]Wenzel, T., Eckerskorn, C., Lottspeich, F., Baumeister, W., 1994. Existence of a molecular ruler in proteasomes suggested by analysis of degradation products. FEBS Lett., 349(2):205-209.