Binding Chaperones

The association of stress proteins with peptide antigens can be explained easily with their function to prevent protein aggregation under stress and physiological conditions by binding to exposed peptide stretches of non-native proteins. Under stress conditions stress proteins of the HSP 70 and 90 family are preventing aggregation of partially denatured and misfolded proteins. Under physiological conditions they prevent immature folding of nascent proteins, assist intracellular protein transport through membranes, guide the assembly of protein complexes and regulate function and degradation of cellular proteins [1-4], Due to these functions stress proteins must have the ability to bind promiscuitively to exposed peptide sequences of partially unfolded, misfolded or nascent proteins.

Indeed, the ability of HSP 70 to bind short stretches of peptides has been described in vitro [52] and recently the existence of a peptide binding pocket has been demonstrated in the HSP 70 crystal structure [53]. HSP 70 binds and releases peptides by cycles of ATP-hydrolysis and ATP binding [54], This was recently demonstrated also for immunogenic peptides in vitro [49]. The reconstituted HSP 70/peptide complexes elicited a peptide-specific CTL response in mice. For HSP 90 evidence for two substrate binding sites has been obtained [55], Peptide binding activity in vitro has also been demonstrated for gp96, the HSP 90 homologue in the endoplasmic reticulum (ER) [49, 56]. The peptide binding of gp96 seems to have a physiological role because it has been shown by peptide translocation assays that gp96 is one of several peptide binding chaperones of the ER [57-59]. The peptide translocation in these studies was TAP-dependent, showing that gp96 associates with peptides in the ER. Together these results show that stress proteins of the HSP 70 and 90 family including gp96 are peptide binding chaperones which can associate with a wide array of cellular peptides.

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