Grp94 is the endoplasmic reticulum (ER) paralog of the Hsp90 chaperone family. It is highly abundant (about 5% of the ER lumen) and known to affect the biosynthesis of several secreted and membrane-bound proteins, such as immunoglobulins and Toll-like receptors. Although Hsp90 chaperones are highly conserved, the crystal structure of Grp94 reveals significant differences in comparison to other members of the Hsp90 family. Furthermore, in contrast to its cytosolic homologs no co-factors of Grp94 have been identified, suggesting that this ER chaperone may have adapted a specialized function. How Grp94 recognizes its client proteins and in what exact step (i.e. protein folding, maturation) it participates is still unknown. I am addressing these questions by performing in vitro studies with suitable substrates. In particular I am interested in the structural aspects of substrate recognition and the conformational changes that occur in Grp94 during substrate binding and release. In addition, I hope to gain insight into the molecular function of Grp94 by studying how the specific conditions present within the ER compartment (i.e. redox potential, calcium concentration) contribute to its conformation and chaperone mechanism.

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