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IMP1 KH1 and KH2 domains create a structural platform with unique RNA recognition and re-modelling properties

DOI: 10.1093/nar/gkz136 DOI Help

Authors: Robert Dagil (University College London) , Neil J Ball (The Francis Crick Institute) , Roksana Ogrodowicz (The Francis Crick Institute) , Fruzsina Hobor (University College London) , Andrew G. Purkiss (The Francis Crick Institute) , Geoff Kelly (The Francis Crick Institute) , Stephen R Martin (The Francis Crick Institute) , Ian A. Taylor (The Francis Crick Institute) , Andres Ramos (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 97

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 13775

Open Access Open Access

Abstract: IGF2 mRNA-binding protein 1 (IMP1) is a key regulator of messenger RNA (mRNA) metabolism and transport in organismal development and, in cancer, its mis-regulation is an important component of tumour metastasis. IMP1 function relies on the recognition of a diverse set of mRNA targets that is mediated by the combinatorial action of multiple RNA-binding domains. Here, we dissect the structure and RNA-binding properties of two key RNA-binding domains of IMP1, KH1 and KH2, and we build a kinetic model for the recognition of RNA targets. Our data and model explain how the two domains are organized as an intermolecular pseudo-dimer and that the important role they play in mRNA target recognition is underpinned by the high RNA-binding affinity and fast kinetics of this KH1KH2–RNA recognition unit. Importantly, the high-affinity RNA-binding by KH1KH2 is achieved by an inter-domain coupling 50-fold stronger than that existing in a second pseudo-dimer in the protein, KH3KH4. The presence of this strong coupling supports a role of RNA re-modelling in IMP1 recognition of known cancer targets.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography

Added On: 27/03/2019 10:48


Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Cancer Non-Communicable Diseases Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)