# Investigating the regulation and substrate processing of ADAMTS13 and ADAMTS7 metalloproteases

> **NIH NIH R35** · OSU CENTER FOR HEALTH SCIENCES · 2022 · $9,311

## Abstract

Project Summary
This MIRA proposal aims to uncover the regulatory mechanisms and substrates for metalloproteases in the
ADAMTS (A Disintegrin And Metalloprotease with ThromboSpondin motifs) family. These proteases are thought
to be involved in many biological processes and some members are known to contribute to important human
diseases. The current study focuses mainly on two members of the ADAMTS family, ADAMTS13 and ADAMTS7.
Project 1 will investigate the allosteric regulation of ADAMTS13, an important regulator of blood clotting. I recently
discovered that ADAMTS13 adopts a quiescent closed conformation and becomes allosterically activated by its
substrate, Von Willebrand Factor (VWF). This proposal outlines a mechanistic approach to study how allosteric
regulation is maintained within ADAMTS13 and disrupted by its interaction with VWF. Leveraging functional,
kinetic, structural and bioinformatic analyses, this project sets to identify the key structural elements of allosteric
regulation in ADAMTS13. The outcomes from this work will improve our understanding of inherited and acquired
blood clotting disorders caused by defects in ADAMTS13. I also anticipate that our investigation of ADAMTS13
will serve as a model to study the regulation of other ADAMTS proteases. Project 2 focuses on ADAMTS7, which
is known to contribute to coronary artery disease by promoting atherosclerosis and inflammation. However, the
substrate targets of ADAMTS7 and its biochemical properties remain poorly understood. Previous attempts to
address these research questions led to conflicting reports in the literature, likely due to the poor quality of
reagents and tools available to study this novel protease. To circumvent these challenges, we will utilize novel
methods in proteomics, enzymology, and protein-protein interactions to delineate biochemical properties and
ideal substrates for ADAMTS7. Newly identified substrates will form the basis of novel biochemical tools to
investigate ADAMTS7 activity and are necessary for future research goals to screen for small molecule inhibitors
of ADAMTS7 that may have translational applications. Summarily, the study of ADAMTS13 and ADAMTS7
enzyme catalysis and regulation lay a foundation for our understanding of thrombotic and bleeding disorders and
cardiovascular and inflammatory diseases, and these outcomes can be applied to study other ADAMTS
proteases. More importantly, the MIRA offers the principal investigator an incredible opportunity to recruit and
mentor students and other trainees from diverse backgrounds.

## Key facts

- **NIH application ID:** 10592685
- **Project number:** 3R35GM142926-01S1
- **Recipient organization:** OSU CENTER FOR HEALTH SCIENCES
- **Principal Investigator:** Joshua Mutambuki Muia
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $9,311
- **Award type:** 3
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592685

## Citation

> US National Institutes of Health, RePORTER application 10592685, Investigating the regulation and substrate processing of ADAMTS13 and ADAMTS7 metalloproteases (3R35GM142926-01S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10592685. Licensed CC0.

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