# Mechanism by which the Grp94 molecular chaperone folds insulin-like growth factors

> **NIH NIH R01** · BRANDEIS UNIVERSITY · 2022 · $37,359

## Abstract

Project Summary
The endoplasmic reticulum (ER) chaperone Grp94 is required for the correct folding and secretion of insulin-like
growth factors (IGF), but the underlying mechanism is not understood. Our goal is to discover how Grp94 assists
the folding of IGF proteins. Grp94 is a member of the Hsp90 chaperone family, which require ATP-driven
conformational cycling to chaperone their “client proteins”. Many oncogenic proteins depend on Hsp90 for their
function. As a result, ATP-competitive inhibitors of Hsp90 have been extensively investigated as anti-cancer
drugs. Although cytosolic Hsp90s were the first intended targets of inhibitors in clinical trials, Grp94 is receiving
increasing attention as a drug target. Grp94 can receive clients from BiP, the Hsp70-family chaperone in the ER.
Through a chance discovery, we have found that the combination of BiP and Hsp90 inhibitors locks Grp94 in a
novel conformation, a state apparently poised for client transfer from BiP to Grp94. Client transfer from BiP to
Grp94 requires two sequential steps: handover of the client from BiP to Grp94, followed by BiP dissociation from
the ternary complex. Our first hypothesis is that Hsp90 inhibitors block both steps: Hsp90 inhibitors stall Grp94
and BiP in a client transfer state because ATP-dependent conformational changes of Grp94 are required
to handover the client from BiP and then displace BiP from Grp94. We will test this hypothesis with IGF2,
as we have discovered that this Grp94 client also has a well-defined BiP binding site. Aim1: Determine whether
ATP-dependent conformational changes of Grp94 cause BiP to handover a bound client protein, and whether
Hsp90 inhibitors disrupt this client-transfer function. Aim2: Determine whether ATP-dependent conformational
changes of Grp94 are required to actively displace BiP from Grp94. Aims 1&2 will test a unified mechanism that
can explain how Hsp90 inhibitors disrupt Grp94 function, but does not explain what essential chaperoning
function is provided by BiP and Grp94 for IGF proteins. We have discovered that IGF2 forms dynamic oligomers.
Similar to other peptide hormones that are known to oligomerize, this self-association may enable IGF2 to be
effectively concentrated and packaged prior to its export to the Golgi. Despite a plausible biological role for IGF2
oligomerization, we have also observed that IGF2 can transition from dynamic reversible oligomers to irreversible
aggregates. Thus, our second hypothesis is that the essential chaperoning function of BiP and Grp94 is to
maintain a dynamic oligomerization state of IGF2. This idea is tested in Aim3: Determine the influence of
Grp94 and BiP on the oligomerization properties of ProIGF2.

## Key facts

- **NIH application ID:** 10612146
- **Project number:** 3R01GM115356-08S1
- **Recipient organization:** BRANDEIS UNIVERSITY
- **Principal Investigator:** Timothy Oliver Street
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,359
- **Award type:** 3
- **Project period:** 2015-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10612146

## Citation

> US National Institutes of Health, RePORTER application 10612146, Mechanism by which the Grp94 molecular chaperone folds insulin-like growth factors (3R01GM115356-08S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10612146. Licensed CC0.

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