Dataset Information

Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity

ABSTRACT: The transcriptional co-activator and acetyltransferase p300 is required for fundamental cellular processes, including differentiation and growth. Here, we report that p300 forms phase separated condensates in the cell nucleus. The phase separation ability of p300 is regulated by autoacetylation and relies on its catalytic core components, including the HAT domain, the autoinhibition loop, and bromodomain. p300 condensates sequester chromatin components, such as histone H3 tail and DNA, and are amplified through binding of p300 to the nucleosome. The catalytic HAT activity of p300 is decreased due to occlusion of the active site in the phase separated droplets, a large portion of which co-localizes with chromatin regions enriched in H3K27me3. Our findings suggest a model in which p300 condensates can act as a storage pool of the protein with reduced HAT activity, allowing p300 to be compartmentalized and concentrated at poised or repressed chromatin regions.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Christopher Ebmeier

LAB HEAD: Tatiana Kutateladze

PROVIDER: PXD026898 | Pride | 2021-08-26

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Acetyl__K_Sites.txt	Txt
	CCE20201014_Yi_Zhang_sample4_11_15_BHZ_SIR_5uL_1pmol_hfx1.raw	Raw
	CCE20201014_Yi_Zhang_sample5_11_16_BZ_WT_5uL_1pmol_hfx1.raw	Raw
	Oxidation__M_Sites.txt	Txt
	allPeptides.txt	Txt

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Publications

Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity.

Zhang Yi Y Brown Kyle K Yu Yucong Y Ibrahim Ziad Z Zandian Mohamad M Xuan Hongwen H Ingersoll Steven S Lee Thomas T Ebmeier Christopher C CC Liu Jiuyang J Panne Daniel D Shi Xiaobing X Ren Xiaojun X Kutateladze Tatiana G TG

Nature communications 20210729 1

The transcriptional co-activator and acetyltransferase p300 is required for fundamental cellular processes, including differentiation and growth. Here, we report that p300 forms phase separated condensates in the cell nucleus. The phase separation ability of p300 is regulated by autoacetylation and relies on its catalytic core components, including the histone acetyltransferase (HAT) domain, the autoinhibition loop, and bromodomain. p300 condensates sequester chromatin components, such as histon ...[more]

PMID: 34326347

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Project description:The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) was discovered more than 2 decades ago and the enzymatic function of these enzymes are established as a major epigenetic regulatory mechanism of gene transcription. Thus, these epigenetic modifiers are involved in multiple diseases and represent attractive targets for therapeutic intervention. While HDAC inhibitors have been developed and approved by the FDA to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged. The HAT paralogs p300 and CBP (here called p300/CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer. Current p300/CBP HAT domain inhibitors including natural products and bisubstrate analogs such as Lys-CoA either lack potency and selectivity or suffer from poor cellular permeability. C646 is widely utilized as a tool to inhibit p300/CBP HAT activity, but its off-target activity and reactivity may limit its cellular specificity. Here, we describe A-485 as a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a pharmacologically active small molecule (A-485) bound to the catalytic active site of p300 HAT domain and demonstrate that A-485 is an acetyl-CoA competitive inhibitor of p300/CBP. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 robustly inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively drugging the catalytic activity of histone acetyltransferases, provide the framework for delineating the enzymatic functions of HATs, and pave the way for the development of novel therapeutics targeting HAT activity.