Major histocompatibility complex (MHC) class I molecules transport intracellular peptides to the cell surface and present them to cytotoxic T cells. The endoplasmic reticulum (ER), Golgi and endosomes each harbour a different quality control system to ensure the structural integrity of the MHC class I molecules, but which molecular features these quality control mechanisms detect are poorly characterised. On the basis of previous reports that the peptide-binding site in suboptimal complexes is highly flexible and partially unfolded, Tim Elliott, Sebastian Springer and colleagues (p. 2885) test their hypothesis that it is this flexibility that is recognised by the cellular quality control mechanisms. The authors designed a new variant of the mouse MHC class I protein H-2Kb in which they artificially restricted the flexibility of the F-pocket region of the binding site in class I molecules by introducing a disulphide bond. The new class I variant, Kb-Y84C, is structurally identical to the wild-type protein and remains fully functional in antigen presentation, but bypasses all three cellular quality control steps; moreover, it has a greatly increased affinity for the small class I subunit β2-microglobulin (β2m). The authors' data show that it is conformational dynamics that dictate the coupling between peptide and β2m binding to the MHC class I molecule, and the resulting immobilisation of MHC class I allows passage through the cellular quality control steps. The authors therefore propose that cellular quality controls monitor the subunit assembly status of class I molecules rather than directly recognising them as peptide-free or suboptimally loaded.
MHC class I proteins are stable without peptide
MHC class I proteins are stable without peptide. J Cell Sci 1 July 2014; 127 (13): e1303. doi:
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