揭示了BRAF激酶调节的域特定和RAS异型特定细节
Tarah Elizabeth Trebino1, Borna Markusic1,2, Haihan Nan1,3
1Rowan University, Glassboro, United States.
eLife
|December 27, 2023
概括
了解BRAF激酶激活揭示了RAS异型如何调节其功能. 这项研究澄清了BRAF.
科学领域:
- 分子生物学分子生物学
- 细胞信号传递 细胞信号传递
- 癌症研究 癌症研究
背景情况:
- BRAF是MAPK通路的关键组成部分,调节细胞生长和分化.
- 突变的BRAF和RAS驱动了人类癌症的很大一部分.
- BRAF激活涉及从一个不活跃的单体到一个活跃的二元体的构造转移,但具体的步骤仍然不清楚.
研究的目的:
- 阐明BRAF法规的特定领域和特定异型细节.
- 调查控制BRAF激活的分子间和分子内相互作用.
- 为癌症治疗开发提供关于BRAF激酶激活机制的见解.
主要方法:
- 拉下测试试剂的测试方法
- 开放表面等离子体共振 (OpenSPR) 是一种
- -交换质谱法 (HDX-MS) 是一种质谱法.
主要成果:
- BRAF特定区域 (BSR) 和富含氨酸的域 (CRD) 对于RAS异型特异性的BRAF激活至关重要.
- 量化了BRAF N-终端和激酶域 (KD) 之间的结合亲缘关系,澄清了它们在自身抑制中的作用.
- 致癌性BRAF-KDD594G突变对N端域的亲和力降低,这表明致病性BRAF的自身抑制降低了.
结论:
- 通过特定的域,BRAF激活以RAS异型依赖的方式受到调节.
- 致病性BRAF突变可能通过逃避自身抑制来发挥作用.
- 这项研究提高了对BRAF激酶激活的理解,有助于开发向癌症治疗方法.
相关概念视频
02:38The Ras Gene
6.2K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
6.2K
01:07MAPK Signaling Cascades
5.5K
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...
5.5K
01:24Small GTPases - Ras and Rho
4.0K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
4.0K
01:22PI3K/mTOR/AKT Signaling Pathway
3.6K
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...
3.6K
01:20The JAK-STAT Signaling Pathway
8.9K
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...
8.9K
01:24Regulation of Angiogenesis and Blood Supply
2.6K
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
2.6K