# Structural Studies of Ion Channel Assembly and Signaling Complexes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $685,689

## Abstract

Project Summary/Abstract
The long-term goals of this project are to develop a high-resolution understanding of ion channel function,
assembly, and regulation. Our studies focus on uncovering the architectural foundations that underlie the
modulation and assembly of channels from the voltage-gated ion channel (VGIC) superfamily and seek to
address the fundamental question of how these multi-subunit protein complexes are assembled into properly
functioning forms. There are exemplar structures of representatives of most major VGIC classes that reveal a
shared, intricately assembled, multi-domain architecture. Although it has been appreciated for decades that
assembly of such proteins is critical for their proper function, there has been no direct structural information to inform
how such complicated multi-unit assembles are put together or whether they interact with chaperone proteins that aid in
their assembly. Among VGICs, the high-voltage activated class of voltage-gated calcium channels (CaV1s and
CaV2s) represent a paradigmatic case whose function and trafficking is powerfully shaped by interactions
between pore-forming CaV1 or CaV2 CaVa1 and auxiliary CaVb and CaVa2d subunits. Our studies focus on the
first known structure of an ion channel:chaperone complex, recently determined by our lab, comprising the brain
and heart CaV1.2 channel, CaVb3, and a nine subunit membrane protein chaperone assembly known as the
Endoplasmic reticulum Membrane protein Complex (EMC). Binding to the EMC chaperone appears to prepare
the CaVa1/CaVb pair for handoff to the CaVa2d to complete channel assembly. We aim to understand which
EMC:channel interactions are important for channel biogenesis, how disease mutations affect EMC:CaV interactions, and
the factors that drive the channel assembly handoff mechanism. The EMC interaction sites are conserved throughout
the CaV1 and CaV2 families and may be shared by other VGIC superfamily members. A second effort is directed at
defining other VGIC EMC clients and determining if they use common elements to interact with the EMC. Elaboration
of the underlying structural framework of VGIC biogenesis is essential for understanding how VGICs are made
and integrated into intracellular signaling pathways and for developing new ways to control channel function.
Our efforts encompass a multidisciplinary approach that includes biochemical, biophysical, mass spectrometry,
and cryo-electronmicroscopy studies to probe structure and cell biological and electrophysiological
measurements to dissect function. Because of their important roles in human physiology, VGICs are targets for
drugs with great utility for treating cardiac arrhythmias, hypertension, congestive heart failure, epilepsy, and
chronic pain. Thus, understanding their structures mechanisms of assembly at atomic level detail should greatly
assist development of valuable therapeutic agents for a wide range of human ailments.

## Key facts

- **NIH application ID:** 10881506
- **Project number:** 2R01DC007664-16
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** DANIEL L MINOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $685,689
- **Award type:** 2
- **Project period:** 2005-07-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881506

## Citation

> US National Institutes of Health, RePORTER application 10881506, Structural Studies of Ion Channel Assembly and Signaling Complexes (2R01DC007664-16). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10881506. Licensed CC0.

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