标识一个哺乳动物线粒体氨酸输送器的识别
Partha C Krishnamurthy1, Guoqing Du, Yu Fukuda
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105-2794, USA.
Nature
|September 29, 2006
概括
线粒体ATP结合盒载体ABCB6促进了氨酸的运输到线粒体中,激活了血红蛋白生物合成. 沉默ABCB6基因阻断了这一关键过程,挑战了对氨酸运动和血红素调节的先前理解.
科学领域:
- 细胞生物学 细胞生物学
- 生物化学 生物化学
- 遗传学 是一个遗传学.
背景情况:
- 与血红素一样,阴阳性氨酸对生物过程至关重要,但它们在细胞内膜 (尤其是线粒体) 中的移动以及血红素生物合成的调节仍然不清楚.
- 线粒体的氨酸吸收依赖于能量,这表明有活跃的运输机制参与其中.
- 众所周知,ATP结合盒 (ABC) 载体调节了跨膜物质的运动.
研究的目的:
- 为了研究线粒体ABC载体ABCB6在线粒体膜上氨酸转移中的作用.
- 阐明ABCB6,氨酸运输和血红素生物合成之间的功能联系.
- 挑战关于细胞内氨酸动态和血红素合成调节的现有范式.
主要方法:
- 分析ABCB6信使RNA (mRNA) 和人类和小鼠细胞中的蛋白质表达在不同的细胞氨酸水平下.
- 数据库搜索人类骨髓,红色素细胞和胎儿肝脏中的ABCB6mRNA表达,以及小鼠胚胎肝脏中的ABCb6表达.
- 实验验证了ABCB6在线粒体外膜的局部化.
- 在具有功能性和沉默的Abcb6基因的细胞中评估线粒体的氨酸吸收和de novo氨酸生物合成.
主要成果:
- ABCB6表达 (mRNA和蛋白质) 在响应细胞皮林的升高时受到上调.
- ABCB6定位在线粒体外膜上,对于线粒体的氨酸吸收是必不可少的.
- 由ABCB6介导的线粒体氨酸的吸收,触发了新的氨酸生物合成.
- 沉默Abcb6基因可以抑制线粒体的氨酸吸收和随后的血红蛋白生物合成.
结论:
- ABCB6是氨酸进入线粒体的关键载体.
- 线粒体ABCB6介导的氨酸吸收是一个关键的步骤,激活de novo血红素生物合成.
- 这些发现需要重新评估控制细胞内氨酸运输和血红蛋白合成调节的机制.
相关概念视频
Mitochondrial Protein Sorting
Mitochondria are double-membrane organelles of the eukaryotes involved in cellular metabolism, signaling, ATP synthesis, and programmed cell death. Each of these processes requires specific proteins and enzymes that must be correctly sorted to the right mitochondrial subcompartment for the proper functioning of the organelle.
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
Most of these mitochondrial proteins are encoded by the nucleus and imported to the mitochondria as unfolded or loosely folded precursors. Mitochondrial precursors...
Mitochondrial Precursor Proteins
Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70 chaperones are targetted to TOM20-TOM22 receptor complexes.
Most of the mitochondrial precursors...
Most of the mitochondrial precursors...
Translocation of Proteins into the Mitochondria
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Porin Insertion in the Outer Mitochondrial Membrane
Porins are beta-barrel proteins translocated to the mitochondrial outer membrane through the TOM complex into the intermembrane space. Porin precursors bind TIM chaperones within the intermembrane space and are guided to the Sorting and Assembly Machinery complex or SAM complex on the outer mitochondrial membrane.
Three models describe the assembly of porins by the SAM complex and their insertion into the outer membrane. Model 1 suggests that porins are assembled outside the SAM channel as the...
Three models describe the assembly of porins by the SAM complex and their insertion into the outer membrane. Model 1 suggests that porins are assembled outside the SAM channel as the...
Protein Transport into the Inner Mitochondrial Membrane
Nuclear encoded mitochondrial precursors are imported to the inner membrane in a multistep process involving two separate translocons, TIM22 and TIM23. TIM23 is a cation-selective pore that remains closed by the N terminal segment of the protein. Negative charges on the TIM23 act as a receptor for the incoming precursor, pulling the positively charged matrix-targeting sequence for peptide insertion and translocation.
Transport of mitochondrial precursors across the TIM23 channel is driven by...
Transport of mitochondrial precursors across the TIM23 channel is driven by...
Structure of Porins
Mitochondria, chloroplasts, and gram-negative bacteria have transmembrane, beta-barrel proteins called porins to mediate the free diffusion of ions and metabolites across the membrane. Mitochondrial porin precursors contain conserved amino acid sequences called beta signals at their C-terminal. Beta signals have a motif of PoXGXXHyXHy (Po-Polar, X-Any amino acid, G-Glycine, Hy-LargeHydrophobic), which are crucial for precursor recognition to initiate precursor assembly. Beta-barrel precursors...


