# Assembly Chaperone Complex for Membrane Proteins in the Endoplasmic Reticulum

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $378,350

## Abstract

Project Description
There is a significant knowledge gap in understanding how multi-subunit membrane proteins are
inserted, folded, and assembled in the membrane of the endoplasmic reticulum (ER), a cellular
organelle for protein quality control with the assistance of molecular chaperones. We use γ-
aminobutyric acid type A (GABAA) receptors to answer this question. The GABAA receptors, the primary
inhibitory neurotransmitter-gated ion channels in the mammalian central nervous systems, are a
pentameric protein complex. Despite extensive research on GABAA receptors physiology on the plasma
membrane and their role in controlling the inhibition-excitation balance in neural circuits, little effort has
been made to investigate how the protein homeostasis (proteostasis) network regulates the folding and
assembly of GABAA proteins in the ER. This brings a significant barrier for the treatment of genetic
epilepsies because numerous epilepsy-associated mutations in GABAA receptor subunits cause
subunit protein misfolding in the ER and/or disrupt assembly of the pentameric complex, leading to
decreased cell surface localization of the receptor complex and imbalanced neural circuits. Here,
specifically, our affinity purification-mass spectrometry-based proteomics analysis identified a potential
Membrane Protein Assembly Chaperone Complex (MPACC) that interacts with endogenous GABAA
receptors, consisting of heat shock protein 47 (Hsp47) in the ER lumen and the ER membrane protein
complex (EMC) in the ER membrane. In Aim 1, we will test our hypothesis that Hsp47 positively
regulates the assembly of endogenous GABAA receptors in the ER and their functional surface
expression. In Aim 2, we will test our hypothesis that the EMC positively regulates the assembly of
GABAA receptors in the ER membrane and thus their functional surface expression. In Aim 3, we will
manipulate the assembly chaperone complex in the ER to correct the function of pathogenic GABAA
receptors.

## Key facts

- **NIH application ID:** 10145824
- **Project number:** 5R01NS117176-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Tingwei Mu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,350
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145824

## Citation

> US National Institutes of Health, RePORTER application 10145824, Assembly Chaperone Complex for Membrane Proteins in the Endoplasmic Reticulum (5R01NS117176-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10145824. Licensed CC0.

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