A pH-sensitive histidine residue as control element for ligand release from HLA-DR molecules

The differential scanning calorimetry analysis of the murine major histocompatibility complex class II molecule, I-E k , in complex with an antigenic peptide derived from mouse hemoglobin, showed that the thermal stability at the mildly acidic pH is higher than that at the neutral pH. Although the thermal unfolding of I-E k -hemoglobin was irreversible, we extracted the equilibrium thermodynamic parameters from the kinetically controlled heat capacity curves. Both the denaturation temperatures and the enthalpy changes were almost independent of the heating rate over 1°C per min. The linear relation between the denaturation temperature and the calorimetric enthalpy change provided the heat capacity changes, which are classified into one for the mildly acidic pH region and another for the neutral pH region. The equilibrium thermodynamic parameters showed that the increased stability at the mildly acidic pH is because of the entropic effect. These thermodynamic data provided new insight into the current structural model of a transition to an open conformation at the mildly acidic pH, which is critical for the peptide exchange function of major histocompatibility complex class II in the endosome.The major histocompatibility complex (MHC) 1 class II is expressed by professional antigen-presenting cells, which present peptide antigens to CD4 T cells. The newly synthesized MHC class II is transported from the endoplasmic reticulum to acidic compartments as the complex with an invariant chain (Ii). In that complex, the peptide binding groove of MHC class II is occupied by the CLIP, which is part of Ii (1, 2). The antigenic peptides derived from endocytosed proteins, which have been digested by cathepsins into 15-20-amino acid segments, are then loaded onto the peptide-binding groove of the MHC class II in exchange for the CLIP, at an endosomal pH (3-5). The role of the acidic pH is considered to enhance the peptide exchange reaction rate as well as to provide a suitable reaction condition for cathepsins. Finally, the peptide-MHC class II complex is transported from the acidic compartments to the cell surface for the interaction with T cell receptors (6).The acidic pH can change the properties of MHC class II molecules and accelerate the peptide exchange, because of the faster association and/or dissociation reactions (7-9). To understand the pH-dependent functions of MHC class II molecules, it is essential to study their thermodynamic and structural properties. Previous thermal stability analyses have determined the energetic consequences of an alteration in the pH (10, 11). In the present study, we characterized the thermal stability of the murine MHC class II molecule, I-E k , in complex with the peptide, 64 -76, of the d allele of mouse hemoglobin (Hb), using differential scanning calorimetry (DSC) measurements. As compared with other MHC class II molecules, the peptide binding to I-E k is most affected by pH (7). The binding of the fluorescent dye 1-anilinonaphthalene-8-sulfonic acid, a probe for exposed nonpolar si...

Section: Discussionmentioning

confidence: 72%

Thermodynamic Analysis of the Increased Stability of Major Histocompatibility Complex Class II Molecule I-Ek Complexed with an Antigenic Peptide at an Acidic pH

Saito

Sarai

Oda

et al. 2003

“…However, alternative trigger points could also be located outside the binding site. For instance, "His buttons," such as a His-Ile bridge connecting the ␣ 1 -with the ␣ 2 -domain, had been described, which control pH-dependent conformational transitions of the MHC molecule (31). If such a His residue would be the target of the H-bond donor group of the small molecule, the -OH group would play a very active role in the catalytic process, because it would act on the pH sensor similar to an "immobilized" proton.…”

Section: Discussionmentioning

confidence: 99%

“Chemical Analogues” of HLA-DM Can Induce a Peptide-receptive State in HLA-DR Molecules

Marin‐Esteban¹,

Falk

Rötzschke

2004

Self Cite

We had recently identified small molecular compounds that are able to accelerate the ligand exchange reactions of HLA-DR molecules. Here we show that this acceleration is due to the induction of a "peptide-receptive" state. Dissociation experiments of soluble HLA-DR2⅐CLIP (class II-associated invariant chain peptide) complex and peptide-binding studies with "nonreceptive" empty HLA-DR1 and -DR2 molecules revealed that the presence of a small phenolic compound carrying an H-bond donor group (-OH) results in the drastic increase of both off-and on-rates. The rate-limiting step for ligand exchange, the transition of the major histocompatibility complex molecule from a nonreceptive into the receptive state, is normally mediated by interaction with the chaperone HLA-DM. In this respect, the effect of small molecules resembles that of the natural catalyst, except that they are still active at neutral pH. These "chemical analogues" of HLA-DM can therefore modulate the response of CD4؉ T cells by editing the antigen composition of surface-bound class II major histocompatibility complex on living antigen-presenting cells.

“…Histidine residues have been shown to act as pH sensors in nature (25,26). The imidazole side chain of histidine has a pK of 6.…”

Section: Prm-stem Region Modulates Dengue Virus Maturationmentioning

confidence: 99%

The Stem Region of Premembrane Protein Plays an Important Role in the Virus Surface Protein Rearrangement during Dengue Maturation

Zhang

Hunke

Yau

et al. 2012

Background:Dengue virus surface proteins, envelope (E) and pre-membrane (prM), undergo rearrangement during the maturation process at acidic condition. Results: prM-stem region binds tighter to both E protein and lipid membrane when environment becomes acidic. Conclusion: At acidic condition, E proteins are attracted to the membrane-associated prM-stem. Significance: prM-stem region induces virus structural changes during maturation.