GRP78: History

The discovery of heat shock proteins (HSPs) was made by the Italian geneticist Ferruccio Ritossa in 1962 who observed that heat and several chemical stressors, e.g. 2,4-dinitrophenol, azide and dicumarol, induced novel puffing patterns of the polytene chromosomes in the salivary glands of the fruitfly Drosophila melanogaster, characteristic for a profound mRNA synthesis ^13-15. Interestingly, the expressed gene products were identified only 14 years later by the work of Alfred Tissières, consequently termed “heat shock proteins” ¹⁶. Nowadays, it has become widely accepted that this process is common to any living organism ^{17, 18}. HSPs are evolutionary conserved proteins involved in a multitude of cellular processes such as protein folding and removal of detrimental protein aggregates by generating a different cellular homeostasis which is refractory to the inappropriate situation. These molecules have thus been added to the list of molecular chaperones whose conservation and function allows for the longevity throughout the phylogenetic tree ^{17, 19}.

In recent times, HSPs have been classified into various subgroups according to their molecular mass. Grp78, also known as BiP (immunoglobulin heavy-chain binding protein), is a member of the HSP70 family of molecular chaperones. Members of this family were originally characterized as being up-regulated in prokaryotes in response to cellular stress ²⁰. Grp78/BiP was identified in the late 1970s in connection with further chaperones as intracellular polypeptide induced by glucose deprivation ^21-23. In the same decade, Grp78/BiP was found as being up-regulated in cells transformed by avian sarcoma viruses ^23-25. The functional gene of human Grp78/BiP has been isolated and characterized later on by Ting et al. ²⁶. The up-regulation of the Grp78/BiP protein during infection with the paramyxovirus simian virus 5 (SV5) was defined to be caused by the flux of synthesis of the hemagglutinin-neuraminidase (HN) glycoprotein in the early 1990s ²⁷. Studies within the same decade revealed the release of Grp78/BiP from the ER to other cellular compartments, including secretory granules, plasma membranes, and the extracellular milieu ²⁸.

In the late 1990s it became obvious that Grp78/BiP is present on the surface of cancer cells and not on normal cells ²⁹. The crystal structures of four human Hsp70 ATPase domains, including that of Grp78/BiP, were presented for the first time by the group of Herwig Schüler revealing a close similarity to Hsp70-1 ³⁰. Yang et al. recently determined the crystal structures of human Grp78/BiP in its functional ATP-bound state and that of the isolated substrate binding domain (ADP-bound state) with a peptide bound ³¹. These structures together with biochemical analyses gave insight into the molecular processes of substrate recruitment and allosteric interactions in eukaryotic chaperones of the HSP70 family. By using surface plasmon resonance and X-ray crystallography, Hughes and co-workers presented the nucleotide-bound structures and determined the binding affinities to the ATPase domain of Grp78/BiP ^{32, 33}. The findings identify numerous nucleotide-Grp78/BiP interactions within the nucleotide binding domain, making structural information available for enhancing the quality of next generation ATP analogs. In the course of the last years, several diseases have been linked to Grp78/BiP and its interaction partners, such as infectious and neurodegenerative diseases as well as cancer.