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Identities of P2 and P3 Residues of H-2Kb-Bound Peptides Determine Mouse Ly49C Recognition.

Marquez EA, Kane KP - PLoS ONE (2015)

Bottom Line: Despite this ability, little is understood regarding the properties that enable some peptides, when bound to MHC-I molecules, to support Ly49 recognition, but not others.Using RMA-S target cells expressing MHC-I molecules loaded with individual peptides and effector cells expressing the ectodomain of the inhibitory Ly49C receptor, we found that two adjacent amino acid residues, P2 and P3, both buried in the peptide binding groove of H-2Kb, determine mouse Ly49C specificity.If both are aliphatic residues, this is supportive.

View Article: PubMed Central - PubMed

Affiliation: Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
Ly49 receptors can be peptide selective in their recognition of MHC-I-peptide complexes, affording them a level of discrimination beyond detecting the presence or absence of specific MHC-I allele products. Despite this ability, little is understood regarding the properties that enable some peptides, when bound to MHC-I molecules, to support Ly49 recognition, but not others. Using RMA-S target cells expressing MHC-I molecules loaded with individual peptides and effector cells expressing the ectodomain of the inhibitory Ly49C receptor, we found that two adjacent amino acid residues, P2 and P3, both buried in the peptide binding groove of H-2Kb, determine mouse Ly49C specificity. If both are aliphatic residues, this is supportive. Whereas, small amino acids at P2 and aromatic amino acids at the P3 auxiliary anchor residue are detrimental to Ly49C recognition. These results resemble those with a rat Ly49 where the identity of a peptide anchor residue determines recognition, suggesting that dependence on specific peptide residues buried in the MHC-I peptide-binding groove may be fundamental to Ly49 peptide selectivity and recognition.

No MeSH data available.


Related in: MedlinePlus

H-2Kb peptide dependent intramolecular interactions that potentially affect H-2Kb and Ly49C association.(A) Comparison between H-2Kb-RGYVYQGL and H-2Kb-SIINFEKL residues that participate in Ly49C interaction. Differences in intramolecular interactions within the H-2Kb that are affected by the peptide bound may be an important factor for the support of receptor and ligand association. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the SIINFEKL peptide is in dark red; the H-2Kb-RGYVYQGL heavy chain is in gray ribbon, the RGYVYQGL peptide is in teal. Hydrogen bonds are shown in black dashed lines. (B) Co-crystal structure of H-2Kb-SIINFEKL and Ly49C. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the β2m in blue ribbon and the SIINFEKL peptide in dark red. The CTLD of the Ly49C monomer is shown in gold ribbon. The figures were generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL, 1KPU for H-2Kb-RGYVYQGL and 3C8K for H-2Kb-SIINFEKL-Ly49C.
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pone.0131308.g007: H-2Kb peptide dependent intramolecular interactions that potentially affect H-2Kb and Ly49C association.(A) Comparison between H-2Kb-RGYVYQGL and H-2Kb-SIINFEKL residues that participate in Ly49C interaction. Differences in intramolecular interactions within the H-2Kb that are affected by the peptide bound may be an important factor for the support of receptor and ligand association. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the SIINFEKL peptide is in dark red; the H-2Kb-RGYVYQGL heavy chain is in gray ribbon, the RGYVYQGL peptide is in teal. Hydrogen bonds are shown in black dashed lines. (B) Co-crystal structure of H-2Kb-SIINFEKL and Ly49C. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the β2m in blue ribbon and the SIINFEKL peptide in dark red. The CTLD of the Ly49C monomer is shown in gold ribbon. The figures were generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL, 1KPU for H-2Kb-RGYVYQGL and 3C8K for H-2Kb-SIINFEKL-Ly49C.

Mentions: Further comparison of H-2Kb bound to SIINFEKL and RGYVYQGL shows different intramolecular interactions that can be of importance to Ly49C association. For example, in the H-2Kb-SIINFEKL complex, Arg111 forms a hydrogen bond with Glu128, but in the H-2Kb-RGYVYQGL complex Arg111 instead shares a hydrogen bond with Glu102 (Fig 7A). This difference in intramolecular interactions, may affect Ly49C binding, since Arg111 shares van der Waals contacts with Met225 in Ly49C, as well as salt bridges with Glu241 in Ly49C; and Glu128 forms salt bridges with Lys221 of Ly49C, as observed in the H-2Kb-SIINFEKL-Ly49C co-crystal structure (Fig 7B). The aforementioned Met225 and Lys221, are part of the α3 helix in Ly49C, a structural motif that can be of importance in detection of the peptide bound to MHC-I, and contributes to H-2Kb recognition and binding affinity, while the peptide non-discriminating Ly49A receptor instead of forming an alpha helix at region L3, contains a disordered loop [14]. Although more receptors need to be examined for their peptide specificity, it would be interesting to define what determines an Ly49 to be peptide specific as opposed to one that is not. Studying the structural specificity of Ly49-MHC-I interactions can be of importance to understand the molecular basis of regulation controlling NK cell effector functions as well as NK cell development. In addition, and equally important, is the identification of natural peptides that are recognized as self by Ly49 molecules, when bound to MHC-I.


Identities of P2 and P3 Residues of H-2Kb-Bound Peptides Determine Mouse Ly49C Recognition.

Marquez EA, Kane KP - PLoS ONE (2015)

H-2Kb peptide dependent intramolecular interactions that potentially affect H-2Kb and Ly49C association.(A) Comparison between H-2Kb-RGYVYQGL and H-2Kb-SIINFEKL residues that participate in Ly49C interaction. Differences in intramolecular interactions within the H-2Kb that are affected by the peptide bound may be an important factor for the support of receptor and ligand association. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the SIINFEKL peptide is in dark red; the H-2Kb-RGYVYQGL heavy chain is in gray ribbon, the RGYVYQGL peptide is in teal. Hydrogen bonds are shown in black dashed lines. (B) Co-crystal structure of H-2Kb-SIINFEKL and Ly49C. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the β2m in blue ribbon and the SIINFEKL peptide in dark red. The CTLD of the Ly49C monomer is shown in gold ribbon. The figures were generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL, 1KPU for H-2Kb-RGYVYQGL and 3C8K for H-2Kb-SIINFEKL-Ly49C.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4493100&req=5

pone.0131308.g007: H-2Kb peptide dependent intramolecular interactions that potentially affect H-2Kb and Ly49C association.(A) Comparison between H-2Kb-RGYVYQGL and H-2Kb-SIINFEKL residues that participate in Ly49C interaction. Differences in intramolecular interactions within the H-2Kb that are affected by the peptide bound may be an important factor for the support of receptor and ligand association. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the SIINFEKL peptide is in dark red; the H-2Kb-RGYVYQGL heavy chain is in gray ribbon, the RGYVYQGL peptide is in teal. Hydrogen bonds are shown in black dashed lines. (B) Co-crystal structure of H-2Kb-SIINFEKL and Ly49C. Figure shows the H-2Kb-SIINFEKL heavy chain in pink ribbon, the β2m in blue ribbon and the SIINFEKL peptide in dark red. The CTLD of the Ly49C monomer is shown in gold ribbon. The figures were generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL, 1KPU for H-2Kb-RGYVYQGL and 3C8K for H-2Kb-SIINFEKL-Ly49C.
Mentions: Further comparison of H-2Kb bound to SIINFEKL and RGYVYQGL shows different intramolecular interactions that can be of importance to Ly49C association. For example, in the H-2Kb-SIINFEKL complex, Arg111 forms a hydrogen bond with Glu128, but in the H-2Kb-RGYVYQGL complex Arg111 instead shares a hydrogen bond with Glu102 (Fig 7A). This difference in intramolecular interactions, may affect Ly49C binding, since Arg111 shares van der Waals contacts with Met225 in Ly49C, as well as salt bridges with Glu241 in Ly49C; and Glu128 forms salt bridges with Lys221 of Ly49C, as observed in the H-2Kb-SIINFEKL-Ly49C co-crystal structure (Fig 7B). The aforementioned Met225 and Lys221, are part of the α3 helix in Ly49C, a structural motif that can be of importance in detection of the peptide bound to MHC-I, and contributes to H-2Kb recognition and binding affinity, while the peptide non-discriminating Ly49A receptor instead of forming an alpha helix at region L3, contains a disordered loop [14]. Although more receptors need to be examined for their peptide specificity, it would be interesting to define what determines an Ly49 to be peptide specific as opposed to one that is not. Studying the structural specificity of Ly49-MHC-I interactions can be of importance to understand the molecular basis of regulation controlling NK cell effector functions as well as NK cell development. In addition, and equally important, is the identification of natural peptides that are recognized as self by Ly49 molecules, when bound to MHC-I.

Bottom Line: Despite this ability, little is understood regarding the properties that enable some peptides, when bound to MHC-I molecules, to support Ly49 recognition, but not others.Using RMA-S target cells expressing MHC-I molecules loaded with individual peptides and effector cells expressing the ectodomain of the inhibitory Ly49C receptor, we found that two adjacent amino acid residues, P2 and P3, both buried in the peptide binding groove of H-2Kb, determine mouse Ly49C specificity.If both are aliphatic residues, this is supportive.

View Article: PubMed Central - PubMed

Affiliation: Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.

ABSTRACT
Ly49 receptors can be peptide selective in their recognition of MHC-I-peptide complexes, affording them a level of discrimination beyond detecting the presence or absence of specific MHC-I allele products. Despite this ability, little is understood regarding the properties that enable some peptides, when bound to MHC-I molecules, to support Ly49 recognition, but not others. Using RMA-S target cells expressing MHC-I molecules loaded with individual peptides and effector cells expressing the ectodomain of the inhibitory Ly49C receptor, we found that two adjacent amino acid residues, P2 and P3, both buried in the peptide binding groove of H-2Kb, determine mouse Ly49C specificity. If both are aliphatic residues, this is supportive. Whereas, small amino acids at P2 and aromatic amino acids at the P3 auxiliary anchor residue are detrimental to Ly49C recognition. These results resemble those with a rat Ly49 where the identity of a peptide anchor residue determines recognition, suggesting that dependence on specific peptide residues buried in the MHC-I peptide-binding groove may be fundamental to Ly49 peptide selectivity and recognition.

No MeSH data available.


Related in: MedlinePlus