A Conformational Change in the Human Major Histocompatibility Complex Protein HLA-DR1 Induced by Peptide Binding

Zarutskie, Jennifer A.; Sato, Aaron K.; Rushe, Mia; Chan, Iat C.; Lomakin, Aleksey; Benedek, George B.; Stern, Lawrence J.

doi:10.1021/bi983048m

Cited by 83 publications

(120 citation statements)

References 62 publications

(101 reference statements)

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“…To further investigate the conformational differences between DR1-WT, DR1-A1L9, and DR1-A1, we performed gel filtration and dynamic light scattering analyses, as described previously (51). Surprisingly, we observed a slight but consistent difference in the elution volume of DR1-A1 compared with DR1-WT, indicative of a slightly larger apparent size (Fig.…”

Section: Dr1-a1 Shows Altered Hydrodynamic Behavior and Increased Radmentioning

confidence: 68%

Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide

Yin

Trenh

Guce

et al. 2014

Journal of Biological Chemistry

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Background: HLA-DM-mediated peptide exchange is a key factor in epitope selection, but how HLA-DM selects peptides for editing is not known. Results: Peptide complexes sensitive to HLA-DM editing exhibited conformational alterations. Conclusion: HLA-DM efficiently identifies unstable complexes by sensing MHCII-peptide conformations. Significance: These data emphasize HLA-DM as a conformational editor and provide novel mechanistic insight into its function.

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Section: Dr1-a1 Shows Altered Hydrodynamic Behavior and Increased Radmentioning

confidence: 68%

Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide

Yin

Trenh

Guce

et al. 2014

Journal of Biological Chemistry

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“…It has been suggested that peptide binding to empty MHC proteins occurs with rapid formation of a loosely bound intermediate complex which then slowly converts to a compact, peptide-loaded, conformation (31,33). Hydrodynamic studies showing that the radius of empty DR1 is 10-20% larger than for the stable, peptide-loaded complex support the existence of an "open" empty state which may be able to loosely bind peptides until conversion to the stable "compact" peptide-loaded conformation (42). For a murine class II MHC molecule, short-and long-lived MHCpep conformers were found in a pHdependent equilibrium (52).…”

Section: Discussionmentioning

confidence: 99%

A Three-Step Kinetic Mechanism for Peptide Binding to MHC Class II Proteins

2000

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Peptide binding reactions of class II MHC proteins exhibit unusual kinetics, with extremely slow apparent rate constants for the overall association (<100 M -1 s -1 ) and dissociation (<10 -5 s -1 ) processes. Various linear and branched pathways have been proposed to account for these data. Using fluorescence resonance energy transfer between tryptophan residues in the MHC peptide binding site and aminocoumarin-labeled peptides, we measured real-time kinetics of peptide binding to empty class II MHC proteins. Our experiments identified an obligate intermediate in the binding reaction. The observed kinetics were consistent with a binding mechanism that involves an initial bimolecular binding step followed by a slow unimolecular conformational change. The same mechanism is observed for different peptide antigens. In addition, we noted a reversible inactivation of the empty MHC protein that competes with productive binding. The implications of this kinetic mechanism for intracellular antigen presentation pathways are discussed.Proteins encoded by the major histocompatibility complex (MHC) 1 gene locus bind peptide antigens and display them at the cell surface for inspection by the immune system as part of the mechanism by which foreign material in the body is recognized and removed (1). Class II MHC proteins generally are found on specialized immune system cells such as B cells, macrophages, and dendritic cells, but they can be expressed by most cell types in response to inflammation or infection (2). Newly synthesized class II MHC R-and -glycoprotein subunits associate with a chaperonin-like invariant chain protein, which places an extended loop in the class II peptide binding site and directs transport to an endosomal compartment (3). Endosomal proteins cleave the invariant chain, and the bound fragment is exchanged for peptides generated from cell-surface and endocytosed proteins, in a poorly characterized process catalyzed by the peptide-exchange factor HLA-DM (4). MHC-peptide complexes then are transported to the cell surface for inspection by T-cell receptors on CD4 + T lymphocytes. Crystal structures have been determined for several human and murine class II MHC proteins in complex with defined peptides (5-13). In each case, the peptide was bound in a polyproline type II-like conformation, with several side chains projecting into specificity-determining pockets within the overall peptide binding groove, and with many additional contacts between the MHC proteins and the main chain of the bound peptide.Initially, in vitro kinetic measurements of peptide binding to purified class II MHC proteins were interpreted in terms of the simple bimolecular reaction shown in Scheme 1 (14): Physical and chemical characterization of purified class II MHC revealed that they carried complex mixtures of tightly bound endogenous peptides (15-19). The stoichiometry of binding for peptide added to these preparations was quite low. Many of the natural peptide ligands had extremely long half-lives, often on the order of ...

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“…To strengthen the helical conformation, P1 or P2 don't have the breaking pattern observed at Val33. It has been noted that the biophysical properties of protein-binding peptides, such as main chain hydrogen bond forming ability with target protein, sequence length, secondary structures, side-chain/main-chain, salt bridge, [25][26][27][28][29] affect its binding activity directly. In this study, we thus synthesized sequence-modified peptides (P1.1 to 1.5, P2.1 to 2.3 listed in Table 1) based on P1 and P2, to further clarify the sequential characteristics that could influence IL-10 inhibitory activity.…”

Section: Resultsmentioning

confidence: 99%

Inhibitory mechanism of peptides with a repeating hydrophobic and hydrophilic residue pattern on interleukin-10

Wang

Cummins

et al. 2016

Human Vaccines & Immunotherapeutics

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Interleukin 10 (IL-10) is a cytokine that is able to downregulate inflammation. Its overexpression is directly associated with the difficulty in the clearance of chronic viral infections, such as chronic hepatitis B, hepatitis C and HIV infection, and infection-related cancer. IL-10 signaling blockade has been proposed as a promising way of clearing chronic viral infection and preventing tumor growth in animal models. Recently, we have reported that peptides with a helical repeating pattern of hydrophobic and hydrophilic residues are able to inhibit IL-10 significantly both in vitro and in vivo. 1 In this work, we seek to further study the inhibiting mechanism of these peptides using sequence-modified peptides. As evidenced by both experimental and molecular dynamics simulation in concert the N-terminal hydrophobic peptide constructed with repeating hydrophobic and hydrophilic pattern of residues is more likely to inhibit IL10. In addition, the sequence length and the ability of protonation are also important for inhibition activity.

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A Conformational Change in the Human Major Histocompatibility Complex Protein HLA-DR1 Induced by Peptide Binding

Cited by 83 publications

References 62 publications

Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide

Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide

A Three-Step Kinetic Mechanism for Peptide Binding to MHC Class II Proteins

Inhibitory mechanism of peptides with a repeating hydrophobic and hydrophilic residue pattern on interleukin-10

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