8R2D

Integrator cleavage module assembly intermediate

Summary for 8R2D

• Entry DOI: 10.2210/pdb8r2d/pdb
• EMDB information: 18839
• Descriptor: BRCA1-associated ATM activator 1, Integrator complex subunit 9, Integrator complex subunit 11, ... (5 entities in total)
• Functional Keywords: chaperone, integrator complex, nuclear import, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 341058.11

Authors

Sabath, K.,Qiu, C.,Jonas, S. (deposition date: 2023-11-03, release date: 2024-07-31, Last modification date: 2024-08-21)

Primary citation

Sabath, K.,Qiu, C.,Jonas, S.
Assembly mechanism of Integrator's RNA cleavage module.
Mol.Cell, 84:2882-2899.e10, 2024

PubMed Abstract: The modular Integrator complex is a transcription regulator that is essential for embryonic development. It attenuates coding gene expression via premature transcription termination and performs 3'-processing of non-coding RNAs. For both activities, Integrator requires endonuclease activity that is harbored by an RNA cleavage module consisting of INTS4-9-11. How correct assembly of Integrator modules is achieved remains unknown. Here, we show that BRAT1 and WDR73 are critical biogenesis factors for the human cleavage module. They maintain INTS9-11 inactive during maturation by physically blocking the endonuclease active site and prevent premature INTS4 association. Furthermore, BRAT1 facilitates import of INTS9-11 into the nucleus, where it is joined by INTS4. Final BRAT1 release requires locking of the mature cleavage module conformation by inositol hexaphosphate (IP). Our data explain several neurodevelopmental disorders caused by BRAT1, WDR73, and INTS11 mutations as Integrator assembly defects and reveal that IP is an essential co-factor for cleavage module maturation.

PubMed: 39032489
DOI: 10.1016/j.molcel.2024.06.032

Experimental method

ELECTRON MICROSCOPY (3.9 Å)