Daniel Gewirth
University at Buffalo, NY·Biochemistry
Most proteins that end up on the cell surface or are secreted must first fold correctly inside the endoplasmic reticulum (ER), the cell's protein-processing compartment. Grp94, a member of the hsp90 family of chaperones, is a helper protein that guides many of these proteins to maturity.
- Fields
Biochemistry
Biophysics
Pharmacology
- Topics
Grp94
hsp90
molecular chaperones
- Grants
- 1 known grant, through Aug 2028
What they work on
- Produce Grp94, the ER chaperone of the hsp90 family, with controlled glycosylation at each of its sequons (sugar-attachment sites), using the lab's in-cell expression system.
- Test whether specific glycosylation patterns tune Grp94 activity, using the defined glycoforms in Grp94-specific assays in cells and in purified-protein experiments.
- Determine how glycans change Grp94 structure, and visualize how the chaperone captures a client protein, using structural and biochemical tools.
More about the research
Because Grp94 controls so many client proteins, it is an emerging drug target in type 2 diabetes, familial hypercholesterolemia, sepsis, HER2-positive breast cancer and multiple myeloma. An open question is how Grp94 adapts to changing demands in the ER.
Why it matters
Hyperglycosylated Grp94 appears to act as a disease-specific form of the chaperone that helps cancer cells survive. Learning how glycosylation switches Grp94 between its normal and disease forms could allow drugs to target the disease form while sparing the normal one. This could benefit patients with cancers such as HER2-positive breast cancer and multiple myeloma, and possibly those with metabolic or inflammatory diseases.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Smriti Sangwan
Northwestern University, IL·Biochemistry·Early-career
Determine how IRE1, an ER stress sensor, physically connects to the protein-making translational machinery, using single-particle cryo-electron microscopy to resolve the 3D structures involved.
Samuel Stephens
University of Iowa, IA·Physiology
Establish how glucose metabolism in beta cells supplies reducing molecules that control the redox state of the endoplasmic reticulum, using imaging of proinsulin trafficking reporters in human and rodent diabetes models.
Raquel Lieberman
Georgia Institute of Technology, GA·Biochemistry
Screen the baker's yeast gene-deletion library for strains that survive toxic mutant myocilin, to find cellular pathways that make cells vulnerable to this glaucoma protein.
The school
University at Buffalo: 32 labs on PI Pages, $542M a year on research, 316 research doctorates a year.
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