通过支架蛋白调节MYST乙转移酶的基质偏好
Raghuvir N Sengupta1, Oleg Brodsky2, Patrick Bingham1
1Oncology Research and Development, Pfizer, La Jolla, California, USA.
The Journal of biological chemistry
|February 5, 2025
概括
在形成复合体时,MYST家族 lysine acetyltransferase KAT6A 显示了基质特异性的改变. 不复杂的KAT6A准H3K14,而4蛋白复合体更喜欢H3K23,显示出取决于环境的酶调节.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症治疗方法 癌症治疗方法
背景情况:
- MYST家族的氨酸转移酶是关键的转录调节剂,与癌症有关.
- 这些酶形成多蛋白质复合体,影响它们的基因组基质特异性.
- 控制这种选择性的精确机制,特别是对于KAT6A,仍然不完全理解.
研究的目的:
- 研究MYST成员KAT6A.基质偏好的复杂介导变化.
- 为了确定非复杂的KAT6A形式与其4蛋白复合物的基因素基质特异性.
- 阐明蛋白质复合体的形成如何改变KAT6A的功能性质和治疗潜力.
主要方法:
- 确定了分离的MYST域,全长的KAT6A (KAT6AFL) 和KAT6AFL 4-蛋白质复合体 (KAT6AFL 4-复合体) 的基因组基质特异性.
- 使用双基质抑制剂对MYST域的结构分析来建模基质结合.
- 使用H3的稳定状态测试来量化由复杂形成介导的基质偏好变化.
主要成果:
- 不复杂的KAT6A (MYST域和KAT6AFL) 优先乙化H3K14,与前一个甘氨酸对相关.
- 包括BRPF1在内的KAT6AFL4蛋白复合体,显示出对H3K23乙化的明显偏好,与氨酸-氨酸对相关.
- BRPF1作为一个支架,调节KAT6AFL基质偏好大约10倍.
结论:
- 在KAT6A表现出上下文依赖的基因组基质特异性,在复合形成时从H3K14切换到H3K23.
- 通过像BRPF1这样的支架蛋白质调解的蛋白质复合体组装,显著改变了MYST酶的功能.
- 了解这些复杂介导的调制对于开发向癌症疗法至关重要.
相关概念视频
01:30Assembly of Signaling Complexes
5.7K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
5.7K
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K
01:19Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
01:32Chromatin Modification in iPS Cells
1.6K
Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
1.6K
02:41Chromatin Structure Regulates pre-mRNA Processing
6.9K
In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
The chromatin structure, especially...
The chromatin structure, especially...
6.9K
01:45Regulation of Nuclear Protein Sorting
2.4K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
2.4K