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7sn8

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Cryo-EM structure of Drosophila Integrator cleavage module (IntS4-IntS9-IntS11) in complex with IP6

Structural highlights

7sn8 is a 3 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.74Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

INT4_DROME Component of the Integrator complex, a complex involved in the transcription of small nuclear RNAs (snRNA) and their 3'-box-dependent processing (PubMed:21078872, PubMed:23097424). Involved in the 3'-end processing of the U7 snRNA, and also the spliceosomal snRNAs U1, U2, U4 and U5 (PubMed:21078872, PubMed:23097424). Essential for development (PubMed:21078872). May mediate recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex (By similarity).[UniProtKB:Q96HW7]^[1] ^[2]

Publication Abstract from PubMed

Integrator is a multi-subunit protein complex associated with RNA polymerase II (Pol II), with critical roles in noncoding RNA 3'-end processing and transcription attenuation of a broad collection of mRNAs. IntS11 is the endonuclease for RNA cleavage, as a part of the IntS4-IntS9-IntS11 Integrator cleavage module (ICM). Here we report a cryo-EM structure of the Drosophila ICM, at 2.74 A resolution, revealing stable association of an inositol hexakisphosphate (IP(6)) molecule. The IP(6) binding site is located in a highly electropositive pocket at an interface among all three subunits of ICM, 55 A away from the IntS11 active site and generally conserved in other ICMs. We also confirmed IP(6) association with the same site in human ICM. IP(6) binding is not detected in ICM samples harboring mutations in this binding site. Such mutations or disruption of IP(6) biosynthesis significantly reduced Integrator function in snRNA 3'-end processing and mRNA transcription attenuation. Our structural and functional studies reveal that IP(6) is required for Integrator function in Drosophila, humans, and likely other organisms.

, PMID:36180473^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ezzeddine N, Chen J, Waltenspiel B, Burch B, Albrecht T, Zhuo M, Warren WD, Marzluff WF, Wagner EJ. A subset of Drosophila integrator proteins is essential for efficient U7 snRNA and spliceosomal snRNA 3'-end formation. Mol Cell Biol. 2011 Jan;31(2):328-41. PMID:21078872 doi:10.1128/MCB.00943-10
↑ Chen J, Ezzeddine N, Waltenspiel B, Albrecht TR, Warren WD, Marzluff WF, Wagner EJ. An RNAi screen identifies additional members of the Drosophila Integrator complex and a requirement for cyclin C/Cdk8 in snRNA 3'-end formation. RNA. 2012 Dec;18(12):2148-56. PMID:23097424 doi:10.1261/rna.035725.112
↑ Lin MH, Jensen MK, Elrod ND, Huang KL, Welle KA, Wagner EJ, Tong L. Inositol hexakisphosphate is required for Integrator function. Nat Commun. 2022 Sep 30;13(1):5742. PMID:36180473 doi:10.1038/s41467-022-33506-3