Glucose-regulated protein 94, also known as
Grp94 or gp96, is an abundant resident endoplasmic reticulum (ER)
lumenal stress protein which together with cytosolic Hsp90 belongs
to the Hsp90 family of molecular chaperones. Grp94 and other resident
soluble proteins of the ER such as members of the Ca(2+) binding
protein subfamily (CaBP), CaBPI and CaBP2 as well as calreticulin,
possesses the COOH-terminal tetrapeptide Lys-Asp-Glu-Leu (KDEL)
which is a sorting signal that is thought to lead to the retention
of these proteins in the pre-Golgi compartments. Grp94 expression
is upregulated by stress conditions such as glucose starvation
and heat shock, which promote protein misfolding or unfolding.
In addition to a homeostatic role in protein folding and assembly,
Grp94 can function in the intracellular trafficking of peptides
from the extracellular space to the MHC class I antigen processing
pathway of antigen presentation cells. Grp94
and Hsp90 share high sequence identity and presumably identical adenosine nucleotide-dependent
modes of regulation. But earlier data suggests that Hsp90 and Grp94 may differ
in their nucleotide binding properties. The Nterminal domain of eukaryotic Hsp90
proteins contains a conserved adenosine nucleotide binding pocket which also
serves as the binding site for the Hsp90 inhibitors geldanamycin and radicicol.
However, the molecular basis for adenosine nucleotide-dependent regulation of
Grp94 remains to be established. Recent data has identified a ligand dependent
regulation of Grp94 function and suggest a model whereby Grp94 function is regulated
through a ligand-dependent conversion of Grp94 from an inactive to an active
conformation.
- back - complete
text - |
