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五聚体 KCTD5/CUL3/Gβγ E3 泛素连接酶复合物的结构与动力学。

Structure and dynamics of a pentameric KCTD5/CUL3/Gβγ E3 ubiquitin ligase complex.

机构信息

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.

Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.

出版信息

Proc Natl Acad Sci U S A. 2024 Apr 23;121(17):e2315018121. doi: 10.1073/pnas.2315018121. Epub 2024 Apr 16.

DOI:10.1073/pnas.2315018121
PMID:38625940
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11047111/
Abstract

Heterotrimeric G proteins can be regulated by posttranslational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and a C-terminal domain, engages CUL3 to form the central scaffold of a cullin-RING E3 ligase complex (CRL3) that ubiquitylates Gβγ and reduces Gβγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3/Gβγ assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5/CUL3 and KCTD5/Gβγ moieties of the structure. CRL3 engages the E3 ligase ARIH1 to ubiquitylate Gβγ in an E3-E3 superassembly, and extension of the structure to include full-length CUL3 with RBX1 and an ARIH1ubiquitin conjugate reveals that some conformational states position the ARIH1ubiquitin thioester bond to within 10 Å of lysine-23 of Gβ and likely represent priming complexes. Most previously described CRL/substrate structures have consisted of monovalent complexes and have involved flexible peptide substrates. The structure of the KCTD5/CUL3/Gβγ complex shows that the oligomerization of a substrate receptor can generate a polyvalent E3 ligase complex and that the internal dynamics of the substrate receptor can position a structured target for ubiquitylation in a CRL3 complex.

摘要

异三聚体 G 蛋白可以通过翻译后修饰来调节，包括泛素化。KCTD5 是一种五聚体底物受体蛋白，由 N 端 BTB 结构域和 C 端结构域组成，它与 CUL3 结合形成 Cullin-RING E3 连接酶复合物（CRL3）的中心支架，该复合物使 Gβγ泛素化，并降低细胞中的 Gβγ 蛋白水平。5:5:5 KCTD5/CUL3/Gβγ 组装体的冷冻电镜结构揭示了一个高度动态的复合物，结构中 KCTD5/CUL3 和 KCTD5/Gβγ 部分之间的旋转超过 60°。CRL3 与 E3 连接酶 ARIH1 结合，在 E3-E3 超组装中使 Gβγ 泛素化，并且将结构扩展到包括全长 CUL3、RBX1 和 ARIH1泛素缀合物，表明某些构象状态将 ARIH1泛素硫酯键定位在 Gβ 的赖氨酸-23 以内 10 Å 的位置，并且可能代表引发复合物。以前描述的大多数 CRL/底物结构都由单价复合物组成，并且涉及柔性肽底物。KCTD5/CUL3/Gβγ 复合物的结构表明，底物受体的寡聚化可以产生多价 E3 连接酶复合物，并且底物受体的内部动力学可以将结构化的靶标定位在 CRL3 复合物中进行泛素化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/01d423aea4b7/pnas.2315018121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/560130fbd5bb/pnas.2315018121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/4b11750c4912/pnas.2315018121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/f20df2053cd9/pnas.2315018121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/838eace09beb/pnas.2315018121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/20df9e481a2b/pnas.2315018121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/01d423aea4b7/pnas.2315018121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/560130fbd5bb/pnas.2315018121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/4b11750c4912/pnas.2315018121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/f20df2053cd9/pnas.2315018121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/838eace09beb/pnas.2315018121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/20df9e481a2b/pnas.2315018121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eedf/11047111/01d423aea4b7/pnas.2315018121fig06.jpg

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