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Peroxisome biogenesis initiated by protein phase separation
Nature ( IF 50.5 ) Pub Date : 2023-05-10 , DOI: 10.1038/s41586-023-06044-1
Rini Ravindran 1 , Isabel O L Bacellar 1, 2 , Xavier Castellanos-Girouard 1 , Haytham M Wahba 1, 3 , Zhenghao Zhang 4, 5 , James G Omichinski 1 , Lydia Kisley 4, 6 , Stephen W Michnick 1
Affiliation  

Peroxisomes are organelles that carry out β-oxidation of fatty acids and amino acids. Both rare and prevalent diseases are caused by their dysfunction1. Among disease-causing variant genes are those required for protein transport into peroxisomes. The peroxisomal protein import machinery, which also shares similarities with chloroplasts2, is unique in transporting folded and large, up to 10 nm in diameter, protein complexes into peroxisomes3. Current models postulate a large pore formed by transmembrane proteins4; however, so far, no pore structure has been observed. In the budding yeast Saccharomyces cerevisiae, the minimum transport machinery includes the membrane proteins Pex13 and Pex14 and the cargo-protein-binding transport receptor, Pex5. Here we show that Pex13 undergoes liquid–liquid phase separation (LLPS) with Pex5–cargo. Intrinsically disordered regions in Pex13 and Pex5 resemble those found in nuclear pore complex proteins. Peroxisomal protein import depends on both the number and pattern of aromatic residues in these intrinsically disordered regions, consistent with their roles as ‘stickers’ in associative polymer models of LLPS5,6. Finally, imaging fluorescence cross-correlation spectroscopy shows that cargo import correlates with transient focusing of GFP–Pex13 and GFP–Pex14 on the peroxisome membrane. Pex13 and Pex14 form foci in distinct time frames, suggesting that they may form channels at different saturating concentrations of Pex5–cargo. Our findings lead us to suggest a model in which LLPS of Pex5–cargo with Pex13 and Pex14 results in transient protein transport channels7.



中文翻译:


蛋白质相分离启动过氧化物酶体生物发生



过氧化物酶体是进行脂肪酸和氨基酸β-氧化的细胞器。罕见病和流行病都是由它们的功能障碍引起的1 。引起疾病的变异基因包括蛋白质转运至过氧化物酶体所需的基因。过氧化物酶体蛋白质输入机制也与叶绿体有相似之处2 ,在将折叠的、直径达 10 nm 的大蛋白质复合物运输到过氧化物酶体3方面具有独特性。目前的模型假设跨膜蛋白形成大孔4 ;然而,到目前为止,尚未观察到孔隙结构。在芽殖酵母酿酒酵母中,最小的转运机制包括膜蛋白 Pex13 和 Pex14 以及货物蛋白结合转运受体 Pex5。在这里,我们展示了 Pex13 与 Pex5-cargo 进行液-液相分离 (LLPS)。 Pex13 和 Pex5 中本质上无序的区域类似于核孔复合蛋白中发现的区域。过氧化物酶体蛋白的输入取决于这些本质上无序区域中芳香残基的数量和模式,这与它们在 LLPS 缔合聚合物模型中作为“贴纸”的作用一致5,6 。最后,成像荧光互相关光谱表明货物输入与 GFP-Pex13 和 GFP-Pex14 在过氧化物酶体膜上的瞬时聚焦相关。 Pex13 和 Pex14 在不同的时间范围内形成焦点,表明它们可能在不同的 Pex5-cargo 饱和浓度下形成通道。我们的研究结果使我们提出了一个模型,其中 Pex5-货物与 Pex13 和 Pex14 的 LLPS 导致瞬时蛋白质转运通道7

更新日期:2023-05-11
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