# Decoding the molecular logic of TPR cochaperones

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $39,466

## Abstract

PROJECT SUMMARY / ABSTRACT
Tetratricopeptide repeat (TPR) cochaperones are a diverse family of adaptor proteins that cooperate with the
heat shock protein (Hsp) 70 and Hsp90 chaperone systems. These modular proteins are composed of their
eponymous TPR domain, which mediates complex formation with the Hsps, and an enzymatic or scaffolding
domain that can aid the chaperone in client recruitment or quality control. The importance of these accessory
functionalities in maintaining protein homeostasis is evidenced by the implication of TPR cochaperones in a wide
range of diseases from neurodegeneration to cancer. However, our understanding of the molecular mechanisms
that underpin substrate recognition by these proteins is incomplete. In particular, there is increasing evidence
that TPR domains can recruit proteins beyond their canonical chaperone binding partners, and the significance
of this alternative pathway is currently unknown. In addition, it is generally difficult to establish substrate
relationships for TPR cochaperones given the compensation that can occur within the protein homeostasis
network following genetic perturbations. Development of chemical probes that can specifically inhibit TPR
cochaperone complexes with high temporal resolution is therefore highly desirable. The effort to develop such
tools would be greatly augmented by an understanding of which molecular features of TPR domains can be
exploited to achieve high affinity and selective binding. The objective of this proposal is to develop a chemical
toolkit that helps solve both of these problems by decoding the molecular logic of interactions between TPR
cochaperones and their substrates. In my first aim, I will develop chemical proteomic tools to profile the binding
of TPR cochaperones and measure changes in substrate association in response to different stimuli. These
probes will also enable the specificity of TPR inhibitors to be assessed in a rapid fashion. In my second aim, I
will refine a predictive scoring function in order to comprehensively identify substrates that are autonomously
recognized by the E3 ligase CHIP. In exploring the molecular determinants of CHIP's interactions with its
substrates, I will also identify features that enable an individual TPR cochaperone to bind ligands that are distinct
from its related family members. This work is significant because it will provide fundamental insights into the
rules governing the biology of TPR cochaperones, and will serve as the bedrock for future substrate discovery
and probe development efforts across this protein family. The proposed studies will also provide a training
environment that is ideally suited to my goal of becoming a translational chemical biologist, with opportunities to
gain experience with state-of-the-art techniques while also cultivating my ability to conduct research
independently.

## Key facts

- **NIH application ID:** 10463466
- **Project number:** 1F31AG077842-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Matthew Callahan
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,466
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463466

## Citation

> US National Institutes of Health, RePORTER application 10463466, Decoding the molecular logic of TPR cochaperones (1F31AG077842-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10463466. Licensed CC0.

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