Researchers from the Hauptman Woodward Medical Research Institute, working in part at SSRL's Beam Line 11-1, have used x-ray diffraction data to confirm a family linkage between the mammalian protein GRP94 and the better known HSP90 proteins, whose functions range from signal transduction to immune response. It is the first high resolution picture of any member of the HSP90 family. Therapies that target GRP94, an essential endoplasmic chaperone (chaperones assist the newly synthesized proteins to achieve their final fold), might play a role in the treatment of immune diseases like sepsis, heart disease, and cancer. The results were published in the October 2007 issue of Molecular Cell.

The structural study and further experiments showed for the first time that GRP94 has a very weak but reproducible ATPase activity. The studies also suggested that the transition from the "twisted V" conformation to one that aligns the catalytic residues was likely to be a key step in the regulation of GRP94 activity. The mammalian member of this HSP90 family is different than those previously studied, which were derived from either bacteria or yeast. The cytoplasmic human Hsp90 exhibits unusually weak ATPase activity, and thus may bear a strong structural resemblance to GRP94. This means that the insights gained by a greater scientific understanding of how GRP94 works will have more direct application to human diseases.

Crystal screening and data collection were carried out using SSRL's user remote-access system, enabling the research group to perform (and control) the experiment from their home laboratory.

Dollins, D.E., Warren, J.J., Immormino, R.M., and Gewirth, D.T. (2007). Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones. Mol Cell 28, 41-56.

To learn more about this research see the full scientific highlight at:
http://www- ssrl.slac.stanford.edu/research/highlights_archive/grp94-nucletide.html