8EJM

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

Summary for 8EJM

• Entry DOI: 10.2210/pdb8ejm/pdb
• Descriptor: ATP-dependent RNA helicase DHX15, SURP and G-patch domain-containing protein 1, ADENOSINE-5'-DIPHOSPHATE, ... (8 entities in total)
• Functional Keywords: complex, helicase, splicing factor, rna binding protein, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 87723.13

Authors

Huang, J.,Tong, L. (deposition date: 2022-09-17, release date: 2022-12-14, Last modification date: 2023-10-25)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)