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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

Structural analysis of peptide amino acid docking into the D-pocket of H-2Kb.The auxiliary anchor residue at position 3 (P3) docks into the shallow D-pocket of H-2Kb formed by residues within the α2-helix. Comparison of P3 in H-2Kb-SIINFEKL and H-2Kb-RGYVYQGL, complexes that do or do not support Ly49C-H-2Kb interaction, respectively. The 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. The figure was generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL and 1KPU for H-2Kb-RGYVYQGL.
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pone.0131308.g004: Structural analysis of peptide amino acid docking into the D-pocket of H-2Kb.The auxiliary anchor residue at position 3 (P3) docks into the shallow D-pocket of H-2Kb formed by residues within the α2-helix. Comparison of P3 in H-2Kb-SIINFEKL and H-2Kb-RGYVYQGL, complexes that do or do not support Ly49C-H-2Kb interaction, respectively. The 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. The figure was generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL and 1KPU for H-2Kb-RGYVYQGL.

Mentions: Analysis of the crystal structure of H-2Kb bound to SIINFEKL and RGYVYQGL can shed light into the possible molecular mechanism directing peptide specificity by the P3 residue. The P3 residue occupies the D-pocket which is formed by residues within the floor of the peptide binding groove as well as within the α2-helix: Gln114, Glu152, Leu156 and Tyr159 [34]. Interestingly, the D-pocket is located near the ‘hinge’ region joining the two segmented areas of the α2-helix, a structural component of the heavy chain that provides additional flexibility to accommodate different peptides [35]. Residue Tyr159 appears to have similar positioning in both structures, while Gln114 and Leu156 show slight displacement differences, however the greatest contrast is observed in Glu152 within the B-pocket (Fig 4). The bulky and polar amino acid at the auxiliary anchor residue P3, as with the RGYVYQGL peptide, occupies a larger area and gives rise to hydrogen bond formation with Glu152; while in the SIINFEKL peptide, the uncharged and relatively small size of Ile only results in van der Waals interactions with amino acids in the B-pocket. Interactions at the ‘hinge’ region of the α2-helix, including Glu152, can have an impact on solvent exposed residues in the loops that connect the antiparallel β-strands that form the platform of the groove floor, thereby possibly affecting Ly49C binding to H-2Kb.


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

Marquez EA, Kane KP - PLoS ONE (2015)

Structural analysis of peptide amino acid docking into the D-pocket of H-2Kb.The auxiliary anchor residue at position 3 (P3) docks into the shallow D-pocket of H-2Kb formed by residues within the α2-helix. Comparison of P3 in H-2Kb-SIINFEKL and H-2Kb-RGYVYQGL, complexes that do or do not support Ly49C-H-2Kb interaction, respectively. The 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. The figure was generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL and 1KPU for H-2Kb-RGYVYQGL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493100&req=5

pone.0131308.g004: Structural analysis of peptide amino acid docking into the D-pocket of H-2Kb.The auxiliary anchor residue at position 3 (P3) docks into the shallow D-pocket of H-2Kb formed by residues within the α2-helix. Comparison of P3 in H-2Kb-SIINFEKL and H-2Kb-RGYVYQGL, complexes that do or do not support Ly49C-H-2Kb interaction, respectively. The 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. The figure was generated using CHIMERA UCSF software and PDB IDs IVAC for H-2Kb-SIINFEKL and 1KPU for H-2Kb-RGYVYQGL.
Mentions: Analysis of the crystal structure of H-2Kb bound to SIINFEKL and RGYVYQGL can shed light into the possible molecular mechanism directing peptide specificity by the P3 residue. The P3 residue occupies the D-pocket which is formed by residues within the floor of the peptide binding groove as well as within the α2-helix: Gln114, Glu152, Leu156 and Tyr159 [34]. Interestingly, the D-pocket is located near the ‘hinge’ region joining the two segmented areas of the α2-helix, a structural component of the heavy chain that provides additional flexibility to accommodate different peptides [35]. Residue Tyr159 appears to have similar positioning in both structures, while Gln114 and Leu156 show slight displacement differences, however the greatest contrast is observed in Glu152 within the B-pocket (Fig 4). The bulky and polar amino acid at the auxiliary anchor residue P3, as with the RGYVYQGL peptide, occupies a larger area and gives rise to hydrogen bond formation with Glu152; while in the SIINFEKL peptide, the uncharged and relatively small size of Ile only results in van der Waals interactions with amino acids in the B-pocket. Interactions at the ‘hinge’ region of the α2-helix, including Glu152, can have an impact on solvent exposed residues in the loops that connect the antiparallel β-strands that form the platform of the groove floor, thereby possibly affecting Ly49C binding to H-2Kb.

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