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J. Exp. Med.,
Volume 189, Number 11, June 7, 1999 1723-1734
By
From the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston,
Massachusetts 02115
MHC class II molecules and invariant chain assemble at a neutral pH in the endoplasmic reticulum and are transported to a low pH compartment where the invariant chain is trimmed to
the class II-associated invariant chain peptide (CLIP). For many major histocompatibility
complex class II molecules, DM is required for rapid removal of CLIP, which allows binding of
antigenic peptides. Since I-Ag7 confers susceptibility to type I diabetes in NOD mice, the biochemical requirements for peptide loading were examined using soluble I-Ag7 expressed in insect cells. I-Ag7 formed long-lived complexes with naturally processed peptides from transferrin
and albumin, whereas several peptides that represent T cell epitopes of islet autoantigens were
poor binders. I-Ag7-peptide complexes were not sodium dodecyl sulfate (SDS) resistant, indicating that SDS sensitivity may be an intrinsic property of I-Ag7. Complexes of I-Ag7 and CLIP
formed at a neutral pH, but rapidly dissociated at pH 5. This rapid dissociation was due to a
poor fit of M98 of CLIP in the P9 pocket of I-Ag7, since substitution of M98 by a negatively
charged residue greatly enhanced the stability of the complex. These biochemical properties of
I-Ag7 result in the rapid generation of empty molecules at an endosomal pH and have a global
effect on peptide binding by I-Ag7.
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