BiP will not only associate to nascent polypeptides but also may retain affinity for certain folding intermediates that have been fully translocated, although it may yet have to acquire their final conformation or possibly assemble with other subunits to form complexes. How BiP binds to its ligands has been investigated with synthetic peptides, and a role of hydrophobic residues has been established (Blond-Elguindi et al. 1993a,b). This has led to the working hypothesis that BiP binds to exposed hydrophobic regions of proteins. Correctly folded and assembled molecules usually only expose hydrophilic residues at the surface facing the aqueous solutions within cells, and BiP will therefore no longer bind. However, it should be noted that this concept explaining the (lack of) affinity of BiP is currently merely a working hypothesis. It may be well-founded and makes sense, but misfolded proteins are difficult to crystallize and there are no structural data to back up the hypothesis. Currently, the only definition of BiP ligands is that they can be co-immunoprecipitated with BiP after extraction from the cells, and subsequently released from the pellet by addition of ATP in vitro (Munro and Pelham 1986; Vitale et al. 1995) and, reciprocally, that BiP can also be co-precipitated and released when the ligand is precipitated first.
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