Structural properties of MHC class II ligands, implications for the prediction of MHC class II epitopes

TY - JOUR

T1 - Structural properties of MHC class II ligands, implications for the prediction of MHC class II epitopes

AU - Jørgensen, Kasper Winther

AU - Buus, Søren

AU - Nielsen, Morten

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Major Histocompatibility class II (MHC-II) molecules sample peptides from the extracellular space allowing the immune system to detect the presence of foreign microbes from this compartment. Prediction of MHC class II ligands is complicated by the open binding cleft of the MHC class II molecule, allowing binding of peptides extending out of the binding groove. Furthermore, only a few HLA-DR alleles have been characterized with a sufficient number of peptides (100-200 peptides per allele) to derive accurate description of their binding motif. Little work has been performed characterizing structural properties of MHC class II ligands. Here, we perform one such large-scale analysis. A large set of SYFPEITHI MHC class II ligands covering more than 20 different HLA-DR molecules was analyzed in terms of their secondary structure and surface exposure characteristics in the context of the native structure of the corresponding source protein. We demonstrated that MHC class II ligands are significantly more exposed and have significantly more coil content than other peptides in the same protein with similar predicted binding affinity. We next exploited this observation to derive an improved prediction method for MHC class II ligands by integrating prediction of MHC- peptide binding with prediction of surface exposure and protein secondary structure. This combined prediction method was shown to significantly outperform the state-of-the-art MHC class II peptide binding prediction method when used to identify MHC class II ligands. We also tried to integrate N- and O-glycosylation in our prediction methods but this additional information was found not to improve prediction performance. In summary, these findings strongly suggest that local structural properties influence antigen processing and/or the accessibility of peptides to the MHC class II molecule.

AB - Major Histocompatibility class II (MHC-II) molecules sample peptides from the extracellular space allowing the immune system to detect the presence of foreign microbes from this compartment. Prediction of MHC class II ligands is complicated by the open binding cleft of the MHC class II molecule, allowing binding of peptides extending out of the binding groove. Furthermore, only a few HLA-DR alleles have been characterized with a sufficient number of peptides (100-200 peptides per allele) to derive accurate description of their binding motif. Little work has been performed characterizing structural properties of MHC class II ligands. Here, we perform one such large-scale analysis. A large set of SYFPEITHI MHC class II ligands covering more than 20 different HLA-DR molecules was analyzed in terms of their secondary structure and surface exposure characteristics in the context of the native structure of the corresponding source protein. We demonstrated that MHC class II ligands are significantly more exposed and have significantly more coil content than other peptides in the same protein with similar predicted binding affinity. We next exploited this observation to derive an improved prediction method for MHC class II ligands by integrating prediction of MHC- peptide binding with prediction of surface exposure and protein secondary structure. This combined prediction method was shown to significantly outperform the state-of-the-art MHC class II peptide binding prediction method when used to identify MHC class II ligands. We also tried to integrate N- and O-glycosylation in our prediction methods but this additional information was found not to improve prediction performance. In summary, these findings strongly suggest that local structural properties influence antigen processing and/or the accessibility of peptides to the MHC class II molecule.

KW - Alleles

KW - Amino Acid Motifs

KW - Area Under Curve

KW - Computational Biology

KW - Databases, Protein

KW - Epitopes

KW - HLA-DR Antigens

KW - Histocompatibility Antigens Class II

KW - Humans

KW - Ligands

KW - Peptides

KW - Protein Binding

KW - Protein Structure, Secondary

KW - Sequence Analysis, Protein

U2 - 10.1371/journal.pone.0015877

DO - 10.1371/journal.pone.0015877

M3 - Journal article

C2 - 21209859

SN - 1932-6203

VL - 5

SP - e15877

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 12

ER -