GRP78: Protein Type

Grp78, also known as immunoglobulin heavy-chain binding protein or binding-immunoglobulin protein (BiP), belongs to the huge HSP70 family of molecular chaperones ^{1, 2}.  HSP70s are present in the cytosol of pro- and eukaryotes and in any eukaryotic cell compartment, including chloroplasts, mitochondria and ER ^34-37. All HSP70s share a common structure consisting of two conserved functional domains: (i) an N-terminal nucleotide binding domain (NBD) and a C-terminal substrate binding domain (SBD) ^38-40 connected by a short inter-domain linker. This linker has been proposed to mediate homo-oligomerization of Grp78/BiP.

Similar to many other chaperones, Grp78/BiP is a phosphoprotein ⁴¹ whose expression and function can be further modulated by co- and post-translational modifications such as methylation ^{42, 43}, AMPylation ⁴⁴, acetylation ⁴⁵, O-glycosylation ⁴⁶, ADP-ribosylation ⁴⁷ and SUMOylation ⁴⁸. To what extent phosphorylation especially affects the molecular or biological functions of the chaperone is still unclear. Already in 1992, the group of Linda Hendershot described the existence of three interconvertible forms of Grp78/BiP: (i) associated with adapter proteins; (ii) as a free unmodified monomer; or (iii) as a free modified homo-oligomer ⁴⁹. This study clearly demonstrated that free Grp78/BiP primarily exists as homo-oligomer in non-induced cells while in induced cells the monomeric form of free Grp78/BiP predominates. Moreover, ADP-ribosylation and phosphorylation of Grp78/Bip have been found exclusively in unconjugated oligomeric species. Post-translational modifications of the complexed monomeric species can occur after the dissociation of adapter proteins ⁴⁹.