Immunofluorescent detection of GRP78 in mouse fibroblast cells using using Anti-GRP78 (3G12-1G11) monoclonal antibody at 1:100
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.