类固醇受体共激活剂-1（SRC-1）是组蛋白乙酰转移酶

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Steroid receptor coactivator-1 is a histone acetyltransferase

• Thomas E. Spencer
• , Guido Jenster
• , Mark M. Burcin
• , C. David Allis
• , Jianxin Zhou
• , Craig A. Mizzen
• , Neil J. McKenna
• , Sergio A. Onate
• , Sophia Y. Tsai
• , Ming-Jer Tsai
•  & Bert W. O‘Malley

Nature volume 389, pages 194–198 (11 September 1997)

 

 

类固醇受体共激活剂-1（SRC-1）是组蛋白乙酰转移酶

 

主要名词：

P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.

　　CBP and p300 are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun and the adenoviral oncoprotein E1A. The protein encoded by the PCAF gene associates with p300/CBP. It has in vitro and in vivo binding activity with CBP and p300, and competes with E1A for binding sites in p300/CBP. It has histone acetyl transferase activity with core histones and nucleosome core particles, indicating that this protein plays a direct role in transcriptional regulation.^[6]

coactivator：　　A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes.The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression.The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

　　　　　　　　　Some coactivators also have histone acetyltransferase (HAT) activity. HATs form large multiprotein complexes that weaken the association of histones to DNA by acetylating the N-terminal histone tail. This provides more space for the transcription machinery to bind to the promoter, therefore increasing gene expression.

　　　　　　　　　Activators are found in all living organisms, but coactivator proteins are typically only found in eukaryotes because they are more complex and require a more intricate mechanism for gene regulation. In eukaryotes, coactivators are usually proteins that are localized in the nucleus.

Histone acetyltransferases (HATs) ：are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

Family	Organism	Associated complexes	Substrate specificity	Structural features

PCAF

H. sapiens

PCAF

H3, H4

Bromodomain

p300

H. sapiens

H2A, H2B, H3, H4

Bromodomain

CBP

H. sapiens

H2A, H2B, H3, H4

Bromodomain

SRC-1

H. sapiens

ACTR/SRC-1

H3, H4

TAFII250 (TAF1)

S. cerevisiae - H. sapiens

TFIID

H3, H4, (H2A)

Bromodomain

p300/CBP family：

　　The p300/CBP HATs have larger HAT domains (about 500 residues) than those present in the GNAT and MYST families.^[5] They also contain a bromodomain as well as three cysteine/histidine-rich domains that are thought to mediate interactions with other proteins. The structure of p300/CBP is characterized by an elongated globular domain, which contains a seven-stranded β-sheet in the center that is surrounded by nine α-helices and several loops.^[7] The structure of the central core region associated with acetyl-CoA binding is conserved with respect to GNAT and MYST HATs, but there are many structural differences in the regions flanking this central core. Overall, the structural data is consistent with the fact that p300/CBP HATs are more promiscuous than GNAT and MYST HATs with respect to substrate binding.

CREB-binding protein（CBP）：

　　CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBP gene.^[5][6] The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more CREB domains: the nuclear receptor interaction domain (RID), the KIX domain (CREB and MYB interaction domain), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The CREB protein domains, KIX, TAZ1 and TAZ2, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.

EP300（p300）：

　　Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene.^[5] It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.

COS ：are fibroblast-like cell lines derived from monkey kidney tissue. COS cells are obtained by immortalizing CV-1 cells^[1] with a version of the SV40 virus that can produce large T antigen but has a defect in genomic replication.^[2] The CV-1 cell line in turn was derived from the kidney of the African green monkey.^[3]

　　　COS cell lines 指源于非洲绿猴肾成纤维细胞并经SV40病毒基因转化的细胞系.最常用的COS cell lines 是COS-1 and COS-7.它们一般用于病毒和转染研究以及对细胞基因转录的研究中.

 

Gal4 transcription factor is a positive regulator of gene expression of galactose-induced genes.^[1]

　　The Gal4 protein represents a large fungal family of transcription factors, Gal4 family, which includes over 50 members in the yeast Saccharomyces cerevisiae e.g. Oaf1, Pip2, Pdr1, Pdr3, Leu3.

Gal4 domains

　　DNA binding domain：Localised to the N-terminus, belongs to the Zn(2)-C6 fungal family, which forms a Zn – cysteines thiolate cluster. The Gal4 DNA Binding domain recognised specifically response element in GAL1 promoter.

　　Gal4 activation domain：Localised to the C-terminus, belongs to the nine amino acids TransActivation Domain family, 9aaTAD, together with Oaf1, Pip2, Pdr1, Pdr3, but also p53, E2A, MLL.

 transactivation：激活因子(如转录、翻译激活因子等)调控基因表达时，由于蛋白质直接结合或间接作用，引起基因表达激活或增强的调控作用。

 

摘要（本文发表于1997年）

　　类固醇受体和共激活剂蛋白被认为通过促进转录因子组装成稳定的起始结构，而刺激基因表达。

　　然而这些转录因子怎样突破转录抑制的染色质，调节体内的特殊基因网络反式激活还不清楚。

　　有证据表明体内染色质的乙酰化和转录偶联，并且特异的组蛋白乙酰转移酶以DNA结合的组蛋白为目标，从而克服染色质在基因表达上的抑制作用。

　　SRC-1是一些类固醇激素受体超家族的共激活剂。

　　文中得出：SRC-1具有乙酰转移酶活性，并且与另一个HAT，PCAF互作。

　　　　　　　SRC-1的HAT活性在C端并特异性作用于H3和H4。

　　　　　　　因类固醇受体被配体结合，而导致SRC-1和PCAF对特异位点的DNA结合组蛋白乙酰化，是　　类固醇受体结合配体发挥激活功能　　和　　关联的共激活剂增强稳定的起始复合物形成　　的机制，因此增加了转录抑制的染色质模版中特异基因的转录。