A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1


Abstract

Adhesion G-protein-coupled receptors (aGPCRs) play critical roles in diverse cellular processes in neurobiology, development, immunity, and numerous diseases. The lack of molecular understanding of their activation mechanisms, especially with regard to the transmembrane domains, hampers further studies to facilitate aGPCR-targeted drug development. Latrophilin-1/ADGRL1 is a model aGPCR that regulates synapse formation and embryogenesis, and its mutations are associated with cancer and attention-deficit/hyperactivity disorder. Here, we established functional assays to monitor latrophilin-1 function and showed the activation of latrophilin-1 by its endogenous agonist peptide. Via a comprehensive mutagenesis screen, we identified transmembrane domain residues essential for latrophilin-1 basal activity and for agonist peptide response. Strikingly, a cancer-associated mutation exhibited increased basal activity and failed to rescue the embryonic developmental phenotype in transgenic worms. These results provide a mechanistic foundation for future aGPCR-targeted drug design.

Submission Details

ID: idcbzXrn

Submitter: Olha Nazarko

Submission Date: July 9, 2018, 11:55 a.m.

Version: 1

Publication Details
Olha Nazarko, Amanuel Kibrom, Jana Winkler, Katherine Leon, Hannah Stoveken, Gabriel Salzman, Katarzyna Merdas, Yue Lu, Pradnya Narkhede, Gregory Tall, Simone Promel, and Demet Arac,iScience (2018) A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
2JX9 2008-04-29 Solution structure of the Gal_lectin domain of mouse Latrophilin-1 GPCR
2JXA 2008-04-29 Mouse Latrophilin-1 GPCR Gal_lectin domain in complex with Rhamnose
5OVP 2018-03-07 1.5 PDZ domain from rat Shank3 bound to the C terminus of CIRL
4DLQ 2012-02-22 1.85 Crystal structure of the GAIN and HormR domains of CIRL 1/Latrophilin 1 (CL1)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
94.7 Adhesion G protein-coupled receptor L1 O94910 AGRL1_HUMAN
95.5 Adhesion G protein-coupled receptor L1 O97831 AGRL1_BOVIN
95.8 Adhesion G protein-coupled receptor L1 Q80TR1 AGRL1_MOUSE
100.0 Adhesion G protein-coupled receptor L1 O88917 AGRL1_RAT