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中文摘要
翻译
摘要。蛋白质中赖氨酸乙酰化对细胞分化和细胞分化有重要作用
英文摘要
Abstract. Lysine acetylation in proteins contributes significantly to cellular differentiation and development. At the molecular level, effector modules called bromodomains recognize acetylated lysine to facilitate downstream signaling through binding of macromolecular complexes to specific genomic loci. Despite their fundamental role in biology and disease, an unbiased cataloguing of acetylated interacting partners of a specific bromodomain is lacking possibly due to the weak, highly dynamic and context-dependent nature of such interactions. However, such molecular information is essential in delineating precise mechanism by which bromodomains partake in the intricate process of transcriptional regulation in biology and disease. The current proposal outlines a unique strategy termed `Interaction-Based Protein and Promoter Profiling' (IBPP) by introducing a photo-crosslinkable amino acid into the hydrophobic cage of bromodomains to capture transiently interacting partners followed by their proteomic and genomic characterizations. We will apply IBPP to BET bromodomains (BRD2, BRD3, BRD4 and BRDT) to identify their interacting partners from intact cells. Subsequent biochemical validation and functional studies of the newly identified interactome will lead to improved mechanistic understanding of acetylation and bromodomain-mediated gene regulation in normal cells as well as in human malignancies. Salient points of our approach include the ability to identify weak and transient binding partners (because of crosslinking) with high temporal control (because of light as the perturbing agent) of closely related members of BET family (via protein engineering with unnatural mutagenesis) in cell-type specific manner. Since crosslinking occurs in the deeply embedded `aromatic cage' in bromodomains, selectivity in identifying authentic interacting partners is expected to be much higher compared to chromatin immunoprecipitation (ChIP) that relies on formaldehyde-based non-selective crosslinking method. Successful implication of IBPP will be invaluable in providing both molecular as well as system level understanding of the dynamic functions of more than sixty bromodomain-containing human proteins.
期刊论文(8)
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Complementary Steric Engineering at the Protein-Ligand Interface for Analogue-Sensitive TET Oxygenases.
用于模拟敏感的TET氧酶的蛋白质配体界面的互补空间工程。
DOI: 10.1021/jacs.8b05283
发表时间: 2018-08-15
期刊: Journal of the American Chemical Society
影响因子: 15
作者: [Sudhamalla B, Wang S, Snyder V, Kavoosi S, Arora S, Islam K]
通讯作者: Islam K
A rapid mass spectrometric method for the measurement of catalytic activity of ten-eleven translocation enzymes.
一种快速质谱法,用于测量十个时期易位酶的催化活性。
DOI: 10.1016/j.ab.2017.06.011
发表时间: 2017-10-01
期刊: Analytical biochemistry
影响因子: 2.9
作者: [Sudhamalla B, Dey D, Breski M, Islam K]
通讯作者: Islam K
Specific Acetylation Patterns of H2A.Z Form Transient Interactions with the BPTF Bromodomain.
H2A.Z 的特定乙酰化模式与 BPTF 布罗莫结构域形成瞬时相互作用。
DOI: 10.1021/acs.biochem.7b00648
发表时间: 2017
期刊: Biochemistry
影响因子: 2.9
作者: [Perell,GabriellaT, Mishra,NeerajK, Sudhamalla,Babu, Ycas,PeterD, Islam,Kabirul, Pomerantz,WilliamCK]
通讯作者: Pomerantz,WilliamCK
DOI: 10.1021/acs.orglett.9b02042
发表时间: 2019-08
期刊: Organic letters
影响因子: 5.2
作者: [Sam Kavoosi;D. Dey;K. Islam]
通讯作者: Sam Kavoosi;D. Dey;K. Islam
Crosslinking-Assisted Substrate Identification for Lysine Demethylases
Crosslinking-Assisted Substrate Identification for Lysine Demethylases
Crosslinking-Assisted Substrate Identification for Lysine Demethylases
Crosslinking-Assisted Substrate Identification for Lysine Demethylases
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