Integrated Structural Modeling of Full-Length LRH-1 Reveals Inter-domain Interactions Contribute to Receptor Structure and Function.
Structure
; 28(7): 830-846.e9, 2020 07 07.
Article
in En
| MEDLINE
| ID: mdl-32433991
ABSTRACT
Liver receptor homolog-1 (LRH-1; NR5A2) is a nuclear receptor that regulates a diverse array of biological processes. In contrast to dimeric nuclear receptors, LRH-1 is an obligate monomer and contains a subtype-specific helix at the C terminus of the DNA-binding domain (DBD), termed FTZ-F1. Although detailed structural information is available for individual domains of LRH-1, it is unknown how these domains exist in the intact nuclear receptor. Here, we developed an integrated structural model of human full-length LRH-1 using a combination of HDX-MS, XL-MS, Rosetta computational docking, and SAXS. The model predicts the DBD FTZ-F1 helix directly interacts with ligand binding domain helix 2. We confirmed several other predicted inter-domain interactions via structural and functional analyses. Comparison between the LRH-1/Dax-1 co-crystal structure and the integrated model predicted and confirmed Dax-1 co-repressor to modulate LRH-1 inter-domain dynamics. Together, these data support individual LRH-1 domains interacting to influence receptor structure and function.
Key words
BS3; Dax1 Dax-1 Nr0b1; benzophenone artificial amino acid; disulfide crosslink mass spectrometry; hydrogen-deuterium exchange mass spectrometry; integrated structural modeling; nuclear lipids; nuclear phospholipid signaling; nuclear receptor lipidomics; small-angle X-ray scattering; ß-catenin CTNNB1
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Cytoplasmic and Nuclear
/
Molecular Dynamics Simulation
Limits:
Humans
Language:
En
Journal:
Structure
Journal subject:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
BIOTECNOLOGIA
Year:
2020
Document type:
Article
Affiliation country:
United States