Structural basis for the acetylation of histone H3K9 and H3K27 mediated by the histone chaperone Vps75 in Pneumocystis carinii

Autor: Deren Lu, Xiaolu Li, Yanshu Dou, Dan Su, Andrew H. Limper, Yiping Chen, Junhong Han, Yang Zhang, Hui Ye
Rok vydání: 2019
Předmět:
Zdroj: Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy, Vol 4, Iss 1, Pp 1-12 (2019)
ISSN: 2059-3635
Popis: Rtt109 is a histone acetyltransferase (HAT) that is a potential therapeutic target in conditioned pathogenic fungi Pneumocystis carinii (P. carinii). The histone chaperone Vps75 can stimulate the Rtt109-dependent acetylation of several histone H3 lysines and preferentially acetylates H3K9 and H3K27 within canonical histone (H3–H4)2 tetramers. Vps75 shows two protein conformations assembled into dimeric and tetrameric forms, but the roles played by multimeric forms of Vps75 in Rtt109-mediated histone acetylation remain elusive. In P. carinii, we identified that Vps75 (PcVps75) dimers regulate H3K9 and H3K27 acetylation by directly interacting with histone (H3–H4)2 tetramers, rather than by forming a Vps75-Rtt109 complex. For PcVps75 tetramers, the major histone-binding surface is buried within a walnut-like structure in the absence of a histone cargo. Based on crystal structures of dimeric and tetrameric forms of PcVps75, as well as HAT assay data, we confirmed that residues 192E, 193D, 194E, 195E, and 196E and the disordered C-terminal tail (residues 224–250) of PcVps75 mediate interactions with histones and are important for the Rtt109 in P. carinii (PcRtt109)-mediated acetylation of H3K9 and H3K27, both in vitro and in yeast cells. Furthermore, expressing PcRtt109 alone or in combination with PcVps75 variants that cannot effectively bind histones could not fully restore cellular growth in the presence of genotoxic agents that block DNA replication owing to the absence of H3K9 and H3K27 acetylation. Together, these data indicate that the interaction between PcVps75 and histone (H3–H4)2 tetramers is a critical regulator of the Rtt109-mediated acetylation of H3K9 and H3K27.
An unexpected interaction offers new hope for pneumonia Structural biology insights into a chromosome-modifying enzyme could aid development of treatments for a potentially lethal form of fungal pneumonia. Pneumocystis carinii is a common cause of this disease in immune-compromised hospital patients, and researchers have focused on an enzyme called Rtt109 as a promising therapeutic target in this species. This enzyme regulates gene expression by chemically modifying chromosome-associated histone proteins, and researchers led by Dan Su and Junhong Han at Sichuan University have now dissected the mechanism underlying this process. They analyzed the structure of a “chaperone” protein, Vps75, which assists Rtt109-mediated histone modification. They learned that Vps75 enables this process by interacting with histones themselves, rather than partnering directly with Rtt109 as predicted. These findings suggest that clinicians could also potentially fight P. carinii infection with drugs that selectively target this Vps75-histone interaction.
Databáze: OpenAIRE
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