马斯特基纳斯的功能和调节:结构建模和疾病突变的洞察力
Michael C Lemke1, Nithin R Avala1, Michael T Rader1
1Department of Pharmacology, University of Virginia, Charlottesville, VA 22903, USA.
Biomedicines
|April 29, 2025
概括
与癌症等疾病相关的MAST激酶从一个原始祖先中多样化. 哺乳动物的MAST表现出各种组织表达,并且可能是14-3-3调节的,突变会影响蛋白质的稳定性.
科学领域:
- 进化生物学是进化的生物学.
- 结构生物学是结构生物学.
- 生物信息学是一种生物信息学.
背景情况:
- MAST激酶是古老的AGC激酶,涉及到人类疾病,包括癌症,糖尿病和神经发育障碍.
- 了解MAST激酶的起源和多样化对于未来的研究和治疗开发至关重要.
研究的目的:
- 使用结构和生物信息学方法阐明MAST激酶的进化起源和多样化.
- 预测疾病相关突变对MAST蛋白稳定性的功能影响.
主要方法:
- 在各种生物体中对MAST系基因酶的序列和数据库分析.
- 集成预测算法和AlphaFold来估计突变对蛋白质稳定性的影响.
主要成果:
- 高级生物具有多个MAST激酶和单个MAST激酶,所有这些都保留了AGC激酶,DUF1908和PDZ域.
- *D. discoideum*和植物中的早期MAST样蛋白显示域损失,而哺乳动物MAST1-4表现出组织特异性的表达和可能的14-3-3调节.
- 在分析中预测,特定突变 (例如,MAST1-L232P,G522E) 可能会破坏MAST蛋白的稳定.
结论:
- MAST和MAST酶从一个共同的原始MAST祖先进化,随后在哺乳动物中扩大和多样化.
- 哺乳动物的MAST激酶可能由14-3-3蛋白调节,而致病突变通常会影响DUF和激酶域内的翻译后修饰位.
- 这项研究为研究MAST激酶调节和开发新药发现策略提供了一个计算框架.
相关概念视频
MAPK Signaling Cascades
5.0K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.0K
Protein Kinases and Phosphatases
12.9K
Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
12.9K
PI3K/mTOR/AKT Signaling Pathway
3.3K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.3K
mTOR Signaling and Cancer Progression
3.7K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.7K
Interactions Between Signaling Pathways
6.2K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K
The JAK-STAT Signaling Pathway
8.5K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
8.5K


