title: Mouse MORC3 is a GHKL ATPase that localizes to H3K4me3 marked chromatin.
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.
authors.affiliation: Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
authors.forename: Sisi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095;
authors.forename: Linda
authors.initials: L
authors.lastname: Yen
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095;
authors.forename: William A
authors.initials: WA
authors.lastname: Pastor
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158;
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Johnston
authors.affiliation: Shanghai Center for Plant Stress Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201602, China;
authors.forename: Jiamu
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095;
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Shew
authors.affiliation: Molecular Biology Institute, University of California, Los Angeles, CA 90095;
authors.forename: Wanlu
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095;
authors.forename: Jamie
authors.initials: J
authors.lastname: Ho
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095;
authors.forename: Bryan
authors.initials: B
authors.lastname: Stender
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095; Molecular Biology Institute, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;
authors.forename: Amander T
authors.initials: AT
authors.lastname: Clark
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158;
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.affiliation: Department of Human and Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; l.clemens-daxinger@lumc.nl pateld@mskcc.org jacobsen@ucla.edu.
authors.forename: Lucia
authors.initials: L
authors.lastname: Daxinger
authors.affiliation: Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; l.clemens-daxinger@lumc.nl pateld@mskcc.org jacobsen@ucla.edu.
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095 l.clemens-daxinger@lumc.nl pateld@mskcc.org jacobsen@ucla.edu.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Jacobsen
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000266:Adenylyl Imidodiphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D016335:Zinc Fingers
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D000266:Adenylyl Imidodiphosphate; D000251:Adenosine Triphosphatases; C551731:MORC3 protein, mouse; D008239:Lysine
keywords: ATPase; X-ray crystallography; histone mark reader; native mass spectrometry