Abstract
Major histocompatibility complex (MHC) class I molecules load peptides in the endoplasmic reticulum in a process during which the peptide cargo is normally optimized in favor of stable MHC-peptide interactions. A dynamic multimolecular assembly termed the peptide-loading complex (PLC) participates in this process and is composed of MHC class I molecules, calreticulin, ERp57, and tapasin bound to the transporter associated with antigen processing (TAP) peptide transporter. We have exploited the observation that the rat MHC class I allele RT1-Aa, when expressed in the rat C58 thymoma cell line, effectively competes and prevents the endogenous RT1-Au molecule from associating with TAP. However, stable RT1-Au molecules are assembled efficiently in competition with RT1-Aa, demonstrating that cargo optimization can occur in the absence of TAP association. Defined mutants of RT1-Aa, which do not allow formation of the PLC, fail to become thermostable in C58 cells. Wild-type RT1-Aa, which does allow PLC formation, also fails to become thermostable in this cell line, which carries the rat TAPB transporter that supplies peptides incompatible for RT1-Aa binding. Full optimization of RT1-Aa requires the presence of the TAP2A allele, which is capable of supplying suitable peptides. Thus, formation of the PLC alone is not sufficient for optimization of the MHC class I peptide cargo.
Highlights
Major histocompatibility complex (MHC)1 class I molecules are composed of two subunits, a heavy chain and a 2-microglobulin (2m), which fold such that the ␣1 and ␣2 domains of the heavy chain form a binding groove capable of accepting short peptides of between 8 –10 amino acids in length
All three mutants of RT1-Aa were stabilized by the presence of peptide, indicating correct folding of the MHC class I molecule by the criterion of peptide-receptiveness (Fig. 1c)
Removal of Asn176 in the ␣2 domain of Ld, leaves the peptide-loading complex (PLC) intact [18], demonstrating that Asn86 bears the crucial glycan unit. Our data extend this observation to a rat MHC class I molecule, with the observation that removal of Asn86 from RT1-Aa prevents formation of the PLC
Summary
Major histocompatibility complex (MHC) class I molecules are composed of two subunits, a heavy chain and a 2-microglobulin (2m), which fold such that the ␣1 and ␣2 domains of the heavy chain form a binding groove capable of accepting short peptides of between 8 –10 amino acids in length. For example, forms a bridge between the MHC class I molecule and TAP and stabilizes TAP in an as yet unknown manner [5,6,7] It is involved in the process of editing, or optimization of peptides loaded into MHC class I [8]. The role of the other redox site during MHC class I assembly remains to be established
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