Structural insights into a novel histone methyltransferase - KMT9

Abstract: Histone lysine methylation is generally catalyzed by SET-domain protein methyltransferases and regulates chromatin structure and gene expression. In this study, we identified human C21orf127 (HEMK2 or N6AMT1) as a novel histone lysine methyltransferase. C21orf127 functions as an obligate heterodimer with TRMT112 and writes the histone mark H4K12me1 in vitro and in vivo, hereafter named lysine methyltransferase 9 (KMT9). Our functional analyses revealed enrichment of C21orf127 (KMT9α) and H4K12me1 at promoters of numerous cell cycle regulators and control of cell cycle progression by KMT9α. Importantly, KMT9α depletion severely affects the proliferation of androgen receptor-dependent as well as castration- and enzalutamide-resistant prostate cancer cells. I solved the high-resolution structure of KMT9α- TRMT112 (KMT9β), which illustrates the molecular basis of the complex formation. KMT9β can stabilize and activate KMT9α by shielding a large hydrophobic surface on KMT9α as well as improving the cofactor SAM binding. In comparison to the reported complex structure of bacterial PrmC-RF1 (homologs of human KMT9-ETF1)1, the histone H411-15K12me bound KMT9 crystal structure reveals that the conserved 122NPPY125 motif in KMT9α interacts with histone H4K12 similarly as RF1 except that Tyr125 shows no direct contact with histone H4K12me. Accordingly, Y125A mutant exhibits comparable enzymatic activity to histone H4 but not to the previously reported protein substrate ETF1. The data link KMT9-mediated H4K12 mono-methylation to androgen-independent prostate cancer cell proliferation. Additional selectivity mechanisms of KMT9 for histone H4K12 can be revealed from my study as well, including the flexibility of the glycine residues surround H4K12, the “12KXG14” motif and the basic 17RHRK20 motif at the N-terminus of histone H4. The structures of KMT9 provide the initial entry point for structure-based KMT9 inhibitor development. Of note, such KMT9 inhibitors might provide a promising paradigm for treating castration-resistant prostate cancer in the future

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells, ISSN: 1545-9985 ; Universität Freiburg, Dissertation, 2019

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2020
• Urheber: Wang, Sheng
• Beteiligte Personen und Organisationen: Einsle, Oliver ; Schüle, Roland ; Jung, Manfred ; Einsle, Oliver ; Schüle, Roland ; Albert-Ludwigs-Universität Freiburg. Fakultät für Chemie und Pharmazie

Weitere Informationen

• DOI: 10.6094/UNIFR/166481
• URN: urn:nbn:de:bsz:25-freidok-1664812
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 25.03.2025, 13:55 MEZ