The Luminal Binding Protein

The luminal binding protein (BiP) is one of many hsp70 proteins spread over all organismal kingdoms, including prokaryotes, as illustrated by the DnaK gene product in Escherichia coli. It is an ER-resident heat shock 70 cognate that is essential for the folding and maturation of newly synthesized secretory proteins (Gething 1999; Kleizen and Braakman 2004). Hsp70 proteins bind to intermediates of protein folding and assembly, misfolded proteins and peptides displaying hydrophobic regions (Blond-Elguindi et al. 1993b; Gething 1999). The classic view on the biological significance of this interaction is to prevent aggregation which could lead to permanent misfolding (Gething et al. 1986; Hurtley et al. 1989; Gething and Sambrook 1992; Hendershot et al. 1996). However, this may only be the most basic function of the interaction and much remains to be discovered.

Within the hsp70 family, BiP is extremely conserved among eukaryotic kingdoms. It was first identified as the glucose regulated protein GRP78 (Pouyssegur et al. 1977) and then as the immunoglobulin heavy chain binding protein (Haas and Wabl 1983). Both were then found to be identical and classified as a major hsp70 cognate (Munro and Pelham 1986). It carries a typical N-terminal ATPase domain and a C-terminal polypeptide binding domain (Gething 1999), but the coding region is supplemented by an additional sig nal peptide for entry into the ER lumen and an ER retention motif (HDEL) to allow recycling from the Golgi apparatus. The latter remains attached permanently whilst the signal peptide is cleaved after ER entry.

In plants, BiP is encoded by several genes, including eight or more iso-forms in Nicotiana tabacum and three in Arabidopsis thaliana. The possible reason for such redundancy has not yet been established. The degree of conservation among different BiP genes is so high that tobacco BiP can functionally complement yeast BiP (Denecke et al. 1991). Two BiP sequences from different kingdoms have a higher sequence similarity than any other hsp70 member within the same species. This suggests that hsp70 members have evolved early in the evolution of eukaryotic cells to accommodate different cellular compartments with this group of protein folding helpers. This chap-erone is one of the best studied proteins of the ER and will thus be discussed in more detail in the following subsections.

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