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Published on: January 26, 2018
Mouse MORC3 is a GHKL ATPase that localizes to H3K4me3 marked chromatin
Sisi Li1, Linda Yen2, William A Pastor2
1Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Abstract:
Microrchidia (MORC) proteins are GHKL (gyrase, heat-shock protein 90, histidine kinase, MutL) ATPases that function in gene regulation in multiple organisms. Animal MORCs also contain CW-type zinc finger domains, which are known to bind to modified histones. We solved the crystal structure of the murine MORC3 ATPase-CW domain bound to the nucleotide analog AMPPNP (phosphoaminophosphonic acid-adenylate ester) and in complex with a trimethylated histone H3 lysine 4 (H3K4) peptide (H3K4me3). We observed that the MORC3 N-terminal ATPase domain forms a dimer when bound to AMPPNP. We used native mass spectrometry to show that dimerization is ATP-dependent, and that dimer formation is enhanced in the presence of nonhydrolyzable ATP analogs. The CW domain uses an aromatic cage to bind trimethylated Lys4 and forms extensive hydrogen bonds with the H3 tail. We found that MORC3 localizes to promoters marked by H3K4me3 throughout the genome, consistent with its binding to H3K4me3 in vitro. Our work sheds light on aspects of the molecular dynamics and function of MORC3.
Insights
Microrchidia (MORC) proteins regulate genes. Researchers found MORC3 binds to H3K4me3 histone marks, localizing to gene promoters and forming dimers in an ATP-dependent manner, revealing its molecular function.
Area of Science:
- Biochemistry
- Molecular Biology
- Epigenetics
Background:
- Microrchidia (MORC) proteins are GHKL ATPases involved in gene regulation.
- Animal MORCs possess CW-type zinc finger domains that interact with modified histones.
Purpose of the Study:
- To elucidate the structural and functional mechanisms of murine MORC3.
- To investigate the interaction between MORC3 and histone H3 trimethylated at lysine 4 (H3K4me3).
Main Methods:
- Crystal structure determination of the MORC3 ATPase-CW domain.
- Native mass spectrometry to analyze protein dimerization.
- In vitro binding assays with H3K4me3 peptides.
Main Results:
- The crystal structure revealed MORC3 bound to AMPPNP and an H3K4me3 peptide.
- MORC3's ATPase domain dimerizes in an ATP-dependent manner.
- The CW domain specifically binds H3K4me3 via an aromatic cage and hydrogen bonds.
Conclusions:
- MORC3 directly binds H3K4me3, a mark associated with active gene promoters.
- ATP binding drives MORC3 dimerization, suggesting a role in its molecular dynamics.
- MORC3 localization to H3K4me3-marked promoters highlights its function in gene regulation.
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