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Boyoun Park - One of the best experts on this subject based on the ideXlab platform.
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a single polymorphic residue within the peptide binding Cleft of mhc class i molecules determines spectrum of tapasin dependence
Journal of Immunology, 2003Co-Authors: Boyoun ParkAbstract:Different HLA class I alleles display a distinctive dependence on tapasin for surface expression and Ag presentation. In this study, we show that the tapasin dependence of HLA class I alleles correlates to the nature of the amino acid residues present at the naturally polymorphic position 114. The tapasin dependence of HLA class I alleles bearing different residues at position 114 decreases in the order of acidity, with high tapasin dependence for acidic amino acids (aspartic acid and glutamic acid), moderate dependence for neutral amino acids (asparagine and glutamine), and low dependence for basic amino acids (histidine and arginine). A glutamic acid to histidine substitution at position 114 allows the otherwise tapasin-dependent HLA-B4402 alleles to load high-affinity peptides independently of tapasin and to have surface expression levels comparable to the levels seen in the presence of tapasin. The opposite substitution, histidine to glutamic acid at position 114, is sufficient to change the HLA-B2705 allele from the tapasin-independent to the tapasin-dependent phenotype. Furthermore, analysis of point mutants at position 114 reveals that tapasin plays a principal role in transforming the Peptide-Binding groove into a high-affinity, peptide-receptive conformation. The natural polymorphisms in HLA class I H chains that selectively affect tapasin-dependent peptide loading provide insights into the functional interaction of tapasin with MHC class I molecules.
Alexander D. Mackerell - One of the best experts on this subject based on the ideXlab platform.
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Tyr66 acts as a conformational switch in the closed-to-open transition of the SHP-2 N-SH2-domain phosphotyrosine-peptide binding Cleft.
BMC Structural Biology, 2007Co-Authors: Olgun Guvench, Alexander D. MackerellAbstract:Background The N-terminal SH2 domain (N-SH2) of the non-receptor tyrosine phosphatase SHP-2 is involved both in localization of SHP-2 by recognition of phosphotyrosine (pY) peptides and self-inhibition of SHP-2 phosphatase activity through the formation of a protein – protein interface with the phosphatase domain. Mutations that disrupt this interface break the coupling between pY-peptide binding Cleft conformation and self-inhibition, thereby increasing both SHP-2 phosphatase activity and pY-peptide binding affinity, and are associated with the congenital condition Noonan syndrome and various pediatric leukemias. To better characterize the molecular process involved in N-SH2 pY-dependent binding, we have applied explicit-solvent molecular dynamics simulations to study the closed-to-open transition of the N-SH2 pY-peptide binding Cleft.
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Tyr66 acts as a conformational switch in the closed-to-open transition of the SHP-2 N-SH2-domain phosphotyrosine-peptide binding Cleft
BMC Structural Biology, 2007Co-Authors: Olgun Guvench, Alexander D. MackerellAbstract:Background The N-terminal SH2 domain (N-SH2) of the non-receptor tyrosine phosphatase SHP-2 is involved both in localization of SHP-2 by recognition of phosphotyrosine (pY) peptides and self-inhibition of SHP-2 phosphatase activity through the formation of a protein – protein interface with the phosphatase domain. Mutations that disrupt this interface break the coupling between pY-peptide binding Cleft conformation and self-inhibition, thereby increasing both SHP-2 phosphatase activity and pY-peptide binding affinity, and are associated with the congenital condition Noonan syndrome and various pediatric leukemias. To better characterize the molecular process involved in N-SH2 pY-dependent binding, we have applied explicit-solvent molecular dynamics simulations to study the closed-to-open transition of the N-SH2 pY-peptide binding Cleft. Results The existence of stable conformations in the left-handed helical and the extended regions of Tyr66 φ/ψ space prevent rapid interconversion of the backbone and create a conformational switch such that Tyr66 in a left-handed helical backbone conformation results in an open Cleft and in an extended backbone conformation results in a closed Cleft. The stable conformations arise from deep, well-localized free-energy minima in the left-handed helical and extended regions of the Tyr66 φ/ψ map. Changing the Tyr66 backbone conformation from extended to left-handed helical induces a closed-to-open transition in the Cleft, and the reverse change in backbone conformation induces the reverse, open-to-closed transition. In the open-Cleft state, weak solvent-exposed interactions involving the sidechains of Tyr66, Asp40, Lys55, and Gln57 serve to anchor the Tyr66 sidechain to the surface of the protein and away from the binding Cleft entrance, thereby facilitating pY-peptide access to the binding Cleft. Conclusion The simulations point to a regulatory role for Tyr66 and surrounding residues in SHP-2 function: mutations at Tyr66, Asp40, Lys55, and/or Gln57 are predicted to break the switching mechanism and negatively impact pY-peptide binding. This in turn would interfere with cellular localization and the coupled SHP-2 phosphatase activity. The structurally well-defined binding Cleft conformations resulting from the switch-like transition suggest the possibility of applying structure-based methods to develop inhibitors of N-SH2 pY-peptide binding to serve as research tools for signal transduction and precursors to therapeutics for SHP-2-related diseases.
Logan W. Donaldson - One of the best experts on this subject based on the ideXlab platform.
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A lack of peptide binding and decreased thermostability suggests that the CASKIN2 scaffolding protein SH3 domain may be vestigial
BMC Structural Biology, 2016Co-Authors: Jamie J. Kwan, Logan W. DonaldsonAbstract:Background CASKIN2 is a neuronal signaling scaffolding protein comprised of multiple ankyrin repeats, two SAM domains, and one SH3 domain. The CASKIN2 SH3 domain for an NMR structural determination because its Peptide-Binding Cleft appeared to deviate from the repertoire of aromatic enriched amino acids that typically bind polyproline-rich sequences.
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A lack of peptide binding and decreased thermostability suggests that the CASKIN2 scaffolding protein SH3 domain may be vestigial
BMC Structural Biology, 2016Co-Authors: Jamie J. Kwan, Logan W. DonaldsonAbstract:Background CASKIN2 is a neuronal signaling scaffolding protein comprised of multiple ankyrin repeats, two SAM domains, and one SH3 domain. The CASKIN2 SH3 domain for an NMR structural determination because its Peptide-Binding Cleft appeared to deviate from the repertoire of aromatic enriched amino acids that typically bind polyproline-rich sequences. Results The structure demonstrated that two non-canonical basic amino acids (K290/R319) in the binding Cleft were accommodated well in the SH3 fold. An K290Y/R319W double mutant restoring the typical aromatic amino acids found in the binding Cleft resulted in a 20 °C relative increase in the thermal stability. Considering the reduced stability, we speculated that the CASKIN2 SH3 could be a nonfunctional remnant in this scaffolding protein. Conclusions While the NMR structure demonstrates that the CASKIN2 SH3 domain is folded, its Cleft has suffered two substitutions that prevent it from binding typical polyproline ligands. This observation led us to additionally survey and describe other SH3 domains in the Protein Data Bank that may have similarly lost their ability to promote protein-protein interactions.
René E.m. Toes - One of the best experts on this subject based on the ideXlab platform.
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Ligandomes obtained from different HLA-class II-molecules are homologous for N- and C-terminal residues outside the Peptide-Binding Cleft
Immunogenetics, 2019Co-Authors: Arieke S.b. Kampstra, Jurgen Heemst, George M. Janssen, Arnoud H. Ru, Menno Lummel, Peter A. Veelen, René E.m. ToesAbstract:Human CD4+ T lymphocytes play an important role in inducing potent immune responses. T cells are activated and stimulated by peptides presented in human leucocyte antigen (HLA)-class II molecules. These HLA-class II molecules typically present peptides of between 12 and 20 amino acids in length. The region that interacts with the HLA molecule, designated as the Peptide-Binding core, is highly conserved in the residues which anchor the peptide to the molecule. In addition, as these peptides are the product of proteolytic cleavages, certain conserved residues may be expected at the N- and C-termini outside the binding core. To study whether similar conserved residues are present in different cell types, potentially harbouring different proteolytic enzymes, the ligandomes of HLA-DRB1*03:01/HLA-DRB > 1 derived from two different cell types (dendritic cells and EBV-transformed B cells) were identified with mass spectrometry and the binding core and N- and C-terminal residues of a total of 16,568 peptides were analysed using the frequencies of the amino acids in the human proteome. Similar binding motifs were found as well as comparable conservations in the N- and C-terminal residues. Furthermore, the terminal conservations of these ligandomes were compared to the N- and C-terminal conservations of the ligandome acquired from dendritic cells homozygous for HLA-DRB1*04:01. Again, comparable conservations were evident with only minor differences. Taken together, these data show that there are conservations in the terminal residues of peptides, presumably the result of the activity of proteases involved in antigen processing.
Olgun Guvench - One of the best experts on this subject based on the ideXlab platform.
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Tyr66 acts as a conformational switch in the closed-to-open transition of the SHP-2 N-SH2-domain phosphotyrosine-peptide binding Cleft.
BMC Structural Biology, 2007Co-Authors: Olgun Guvench, Alexander D. MackerellAbstract:Background The N-terminal SH2 domain (N-SH2) of the non-receptor tyrosine phosphatase SHP-2 is involved both in localization of SHP-2 by recognition of phosphotyrosine (pY) peptides and self-inhibition of SHP-2 phosphatase activity through the formation of a protein – protein interface with the phosphatase domain. Mutations that disrupt this interface break the coupling between pY-peptide binding Cleft conformation and self-inhibition, thereby increasing both SHP-2 phosphatase activity and pY-peptide binding affinity, and are associated with the congenital condition Noonan syndrome and various pediatric leukemias. To better characterize the molecular process involved in N-SH2 pY-dependent binding, we have applied explicit-solvent molecular dynamics simulations to study the closed-to-open transition of the N-SH2 pY-peptide binding Cleft.
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Tyr66 acts as a conformational switch in the closed-to-open transition of the SHP-2 N-SH2-domain phosphotyrosine-peptide binding Cleft
BMC Structural Biology, 2007Co-Authors: Olgun Guvench, Alexander D. MackerellAbstract:Background The N-terminal SH2 domain (N-SH2) of the non-receptor tyrosine phosphatase SHP-2 is involved both in localization of SHP-2 by recognition of phosphotyrosine (pY) peptides and self-inhibition of SHP-2 phosphatase activity through the formation of a protein – protein interface with the phosphatase domain. Mutations that disrupt this interface break the coupling between pY-peptide binding Cleft conformation and self-inhibition, thereby increasing both SHP-2 phosphatase activity and pY-peptide binding affinity, and are associated with the congenital condition Noonan syndrome and various pediatric leukemias. To better characterize the molecular process involved in N-SH2 pY-dependent binding, we have applied explicit-solvent molecular dynamics simulations to study the closed-to-open transition of the N-SH2 pY-peptide binding Cleft. Results The existence of stable conformations in the left-handed helical and the extended regions of Tyr66 φ/ψ space prevent rapid interconversion of the backbone and create a conformational switch such that Tyr66 in a left-handed helical backbone conformation results in an open Cleft and in an extended backbone conformation results in a closed Cleft. The stable conformations arise from deep, well-localized free-energy minima in the left-handed helical and extended regions of the Tyr66 φ/ψ map. Changing the Tyr66 backbone conformation from extended to left-handed helical induces a closed-to-open transition in the Cleft, and the reverse change in backbone conformation induces the reverse, open-to-closed transition. In the open-Cleft state, weak solvent-exposed interactions involving the sidechains of Tyr66, Asp40, Lys55, and Gln57 serve to anchor the Tyr66 sidechain to the surface of the protein and away from the binding Cleft entrance, thereby facilitating pY-peptide access to the binding Cleft. Conclusion The simulations point to a regulatory role for Tyr66 and surrounding residues in SHP-2 function: mutations at Tyr66, Asp40, Lys55, and/or Gln57 are predicted to break the switching mechanism and negatively impact pY-peptide binding. This in turn would interfere with cellular localization and the coupled SHP-2 phosphatase activity. The structurally well-defined binding Cleft conformations resulting from the switch-like transition suggest the possibility of applying structure-based methods to develop inhibitors of N-SH2 pY-peptide binding to serve as research tools for signal transduction and precursors to therapeutics for SHP-2-related diseases.