8EJM

Crystal structure of human DEAH-box helicase DHX15 in complex with SUGP1 G-patch

8EJM の概要

• エントリーDOI: 10.2210/pdb8ejm/pdb
• 分子名称: ATP-dependent RNA helicase DHX15, SURP and G-patch domain-containing protein 1, ADENOSINE-5'-DIPHOSPHATE, ... (8 entities in total)
• 機能のキーワード: complex, helicase, splicing factor, rna binding protein, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 87723.13

構造登録者

Huang, J.,Tong, L. (登録日: 2022-09-17, 公開日: 2022-12-14, 最終更新日: 2023-10-25)

主引用文献

Zhang, J.,Huang, J.,Xu, K.,Xing, P.,Huang, Y.,Liu, Z.,Tong, L.,Manley, J.L.
DHX15 is involved in SUGP1-mediated RNA missplicing by mutant SF3B1 in cancer.
Proc.Natl.Acad.Sci.USA, 119:e2216712119-e2216712119, 2022

PubMed Abstract: is the most frequently mutated spliceosomal gene in cancer. Several hotspot mutations are known to disrupt the interaction of SF3B1 with another splicing factor, SUGP1, resulting in the RNA missplicing that characterizes mutant SF3B1 cancers. Properties of SUGP1, especially the presence of a G-patch motif, a structure known to function by activating DEAH-box RNA helicases, suggest the requirement of such an enzyme in SUGP1 function in splicing. However, the identity of this putative helicase has remained an important unanswered question. Here, using a variety of protein-protein interaction assays, we identify DHX15 as the critical helicase. We further show that depletion of DHX15 or expression of any of several DHX15 mutants, including one implicated in acute myeloid leukemia, partially recapitulates the splicing defects of mutant SF3B1. Moreover, a DHX15-SUGP1 G-patch fusion protein is able to incorporate into the spliceosome to rescue the splicing defects of mutant SF3B1. We also present the crystal structure of the human DHX15-SUGP1 G-patch complex, which reveals the molecular basis of their direct interaction. Our data thus demonstrate that DHX15 is the RNA helicase that functions with SUGP1 and additionally provide important insight into how mutant SF3B1 disrupts splicing in cancer.

PubMed: 36459648
DOI: 10.1073/pnas.2216712119

実験手法

X-RAY DIFFRACTION (1.8 Å)