美国宾夕法尼亚大学Good, Matthew C.报道了使无序蛋白质组装成离散凝聚相的决定因素。相关研究成果于2024年2月5日发表在《自然—化学》。

细胞有许多介观尺度的无膜区室，这些区室容纳特定的生物化学过程并执行不同的细胞功能。这些富含蛋白质和RNA的小体被认为是通过蛋白质和核酸之间的多价相互作用形成的，从而通过液相分离进行分层。含有内在无序区域（IDRs）的蛋白质在无膜细胞器中占主导地位。然而，尚不清楚IDR序列是否单独能够决定不同凝聚相的形成。

该文中，研究人员鉴定了一对在细胞中表达时能够形成空间上不同的缩合物的IDR。当在体外重建时，这些模型蛋白不会共分配，这表明缩合特异性直接编码在多肽序列中。通过计算建模和诱变，确定了控制同源和异型相互作用的氨基酸和链性质，这些氨基酸和链特性引导选择性缩合。这些结果形成了物理化学原理的基础，这些原理可以将IDR的亚细胞组织引导成特定的缩合物，并揭示了可以指导正交无膜隔室构建的IDR代码。

附：英文原文

Title: Determinants that enable disordered protein assembly into discrete condensed phases

Author: Welles, Rachel M., Sojitra, Kandarp A., Garabedian, Mikael V., Xia, Boao, Wang, Wentao, Guan, Muyang, Regy, Roshan M., Gallagher, Elizabeth R., Hammer, Daniel A., Mittal, Jeetain, Good, Matthew C.

Issue&Volume: 2024-02-05

Abstract: Cells harbour numerous mesoscale membraneless compartments that house specific biochemical processes and perform distinct cellular functions. These protein- and RNA-rich bodies are thought to form through multivalent interactions among proteins and nucleic acids, resulting in demixing via liquid–liquid phase separation. Proteins harbouring intrinsically disordered regions (IDRs) predominate in membraneless organelles. However, it is not known whether IDR sequence alone can dictate the formation of distinct condensed phases. We identified a pair of IDRs capable of forming spatially distinct condensates when expressed in cells. When reconstituted in vitro, these model proteins do not co-partition, suggesting condensation specificity is encoded directly in the polypeptide sequences. Through computational modelling and mutagenesis, we identified the amino acids and chain properties governing homotypic and heterotypic interactions that direct selective condensation. These results form the basis of physicochemical principles that may direct subcellular organization of IDRs into specific condensates and reveal an IDR code that can guide construction of orthogonal membraneless compartments.

DOI: 10.1038/s41557-023-01423-7

Source: https://www.nature.com/articles/s41557-023-01423-7