Marapana Danushka, Cobbold Simon A, Pasternak Michal, Shami Gerald J, Ralph Stuart A, Lopaticki Sash, Yousef Jumana, Vaibhav Vineet, Dagley Laura F, Komander David, Cowman Alan F
The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
Department of Medical Biology, The University of Melbourne, Melbourne, 3010, Australia.
Sci Rep. 2025 Jul 1;15(1):21359. doi: 10.1038/s41598-025-05342-0.
Ubiquitination is the key eukaryotic post-translational modification that governs protein degradation, localisation, and activity which is mediated by a concerted enzyme cascade. The largest superfamily of these enzymes include the Cullin-RING-Ligase (CRL) complexes. Plasmodium falciparum, the causative agent of the most severe form of malaria in humans, encodes the critical proteins required for ubiquitination, but we do not yet understand the function of this pathway. Here the P. falciparum CRL complexes were characterised to reveal an essential but minimal repertoire controlled by two Cullin scaffolds. A PfCullin1-linked CRL complex, recruiting a single substrate receptor, was identified as being required for parasite inner-membrane biogenesis and DNA replication. A second CRL complex functioning through a PfCullin4 scaffold was identified that utilised a previously unidentified adaptor protein and receptors to support DNA replication. These results show that the P. falciparum CRL complexes are essential in both nuclear maintenance and membrane integrity.
泛素化是真核生物关键的翻译后修饰，它通过协同作用的酶级联反应介导蛋白质降解、定位和活性。这些酶中最大的超家族包括Cullin-RING连接酶（CRL）复合物。恶性疟原虫是人类最严重疟疾形式的病原体，它编码泛素化所需的关键蛋白质，但我们尚未了解该途径的功能。在此，对恶性疟原虫的CRL复合物进行了表征，以揭示由两个Cullin支架控制的基本但最小的组成部分。一种与PfCullin1相关的CRL复合物，招募单个底物受体，被确定为寄生虫内膜生物发生和DNA复制所必需。还鉴定出了第二种通过PfCullin4支架发挥作用的CRL复合物，它利用一种先前未鉴定的衔接蛋白和受体来支持DNA复制。这些结果表明，恶性疟原虫的CRL复合物在细胞核维持和膜完整性方面都至关重要。
