# Drp1 Structure: Regulatory Domains and Conformational Flexibility

> **NIH NIH F31** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Mitochondria form dynamic networks in cells with a regulated cycle of fission and fusion to meet energy demands.
An imbalance in the cycle has been implicated in a wide range of diseases—from heart failure to cancer.
Dynamin-related protein 1 (Drp1) is the master regulator of fission, and its activity is controlled through several
pathways, including self-assembly regulation, post-translational modifications, partner protein interactions, and
mitochondria outer membrane contact sites enriched in unsaturated cardiolipin. This project seeks to understand
the structure of the Drp1 dimer (the functional unit), and the conformational rearrangements required for helical
assembly of these dimers on lipid templates. I propose to use cryo-EM single particle methods to resolve the
structures of the WT dimer and an assembly defective mutant. These structures will identify dimer interfaces of
the protein in solution and regions of the structure that contribute to the flexibility necessary to assume a wide
range of geometries required for fission. While cryo-EM will identify distinct states of the Drp1 dimer, molecular
dynamic simulations will be used to elucidate conformational motions through intermediate, or transition, states
needed to build larger complexes on mitochondrial membranes. These in silico studies will identify conformation
sampling of Drp1 and other dynamin superfamily proteins. The results will inform future studies by identifying
specific amino acids that confer functional elasticity. Finally, this proposal seeks to resolve Drp1 helical structures
on lipid nanotubes using cryo-EM. The saturation state of lipid acyl chains has been identified as a regulatory
factor for Drp1 recruitment and self-assembly. Multimer formation on saturated and unsaturated lipid templates
will identify helical structure and polymer diameter changes resulting from lipid membrane perturbations. The
conformational changes the dimer must undergo in order to form helical assemblies will provide invaluable insight
into the biophysical properties of Drp1 that contribute to mitochondrial membrane fission.

## Key facts

- **NIH application ID:** 10067828
- **Project number:** 1F31GM139324-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Kristy Rochon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067828

## Citation

> US National Institutes of Health, RePORTER application 10067828, Drp1 Structure: Regulatory Domains and Conformational Flexibility (1F31GM139324-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10067828. Licensed CC0.

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