An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis.


Abstract

Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl 'decoy receptor' that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high-affinity Axl variant caused structural alterations in side chains across the Gas6-Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc fusion, the engineered decoy receptor bound Gas6 with femtomolar affinity, an 80-fold improvement compared to binding of the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Moreover, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.

Submission Details

ID: SRxq6YRp

Submitter: Marie Ary

Submission Date: June 28, 2017, 12:44 p.m.

Version: 1

Publication Details
Kariolis MS;Miao YR;Jones DS 2nd;Kapur S;Mathews II;Giaccia AJ;Cochran JR,Nat Chem Biol (2014) An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis. PMID:25242553
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
5VXZ 2017-06-21 2.3 High-affinity AXL decoy receptor
5U6B 2017-07-26 2.84 Structure of the Axl kinase domain in complex with a macrocyclic inhibitor
4RA0 2014-09-24 3.07 An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis
2C5D 2005-12-19 3.3 Structure of a minimal Gas6-Axl complex

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Tyrosine-protein kinase receptor Axl Ig1 P30530 UFO_HUMAN