Imperial College London
Portrait Picture

Dr Josefin Ahnström

Faculty of Medicine, Department of Immunology and Inflammation

Senior Lecturer in Haematology
 
 
 
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Contact

 

+44 (0)20 3313 4236j.ahnstrom

 
 
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Location

 

5S5Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Al:2022:10.1016/j.bbrep.2022.101263,
author = {Al, Kafri N and Ahnstrom, J and Teraz-Orosz, A and Chaput, L and Singh, N and Villoutreix, BO and Hafizi, S},
doi = {10.1016/j.bbrep.2022.101263},
journal = {Biochemistry and Biophysics Reports},
title = {The first laminin G-like domain of protein S is essential for binding and activation of Tyro3 receptor and intracellular signalling},
url = {http://dx.doi.org/10.1016/j.bbrep.2022.101263},
volume = {30},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The homologous proteins Gas6 and protein S (ProS1) are both natural ligands for the TAM (Tyro3, Axl, MerTK) receptor tyrosine kinases. ProS1 selectively activates Tyro3; however, the precise molecular interface of the ProS1-Tyro3 contact has not been characterised. We used a set of chimeric proteins in which each of the C-terminal laminin G-like (LG) domains of ProS1 were swapped with those of Gas6, as well as a set of ProS1 mutants with novel added glycosylations within LG1. Alongside wildtype ProS1, only the chimera containing ProS1 LG1 domain stimulated Tyro3 and Erk phosphorylation in human cancer cells, as determined by Western blot. In contrast, Gas6 and chimeras containing minimally the Gas6 LG1 domain stimulated Axl and Akt phosphorylation. We performed in silico homology modelling and molecular docking analysis to construct and evaluate structural models of both ProS1-Tyro3 and Gas6-Axl ligand-receptor interactions. These analyses revealed a contact between the ProS1 LG1 domain and the first immunoglobulin domain of Tyro3, which was similar to the Gas6-Axl interaction, and involved long-range electrostatic interactions that were further stabilised by hydrophobic and polar contacts. The mutant ProS1 proteins, which had added glycosylations within LG1 but which were all outside of the modelled contact region, all activated Tyro3 in cells with no hindrance. In conclusion, we show that the LG1 domain of ProS1 is necessary for activation of the Tyro3 receptor, involving protein-protein interaction interfaces that are homologous to those of the Gas6-Axl interaction.
AU  - Al,Kafri N
AU  - Ahnstrom,J
AU  - Teraz-Orosz,A
AU  - Chaput,L
AU  - Singh,N
AU  - Villoutreix,BO
AU  - Hafizi,S
DO  - 10.1016/j.bbrep.2022.101263
PY  - 2022///
SN  - 2405-5808
TI  - The first laminin G-like domain of protein S is essential for binding and activation of Tyro3 receptor and intracellular signalling
T2  - Biochemistry and Biophysics Reports
UR  - http://dx.doi.org/10.1016/j.bbrep.2022.101263
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000798374700009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.sciencedirect.com/science/article/pii/S2405580822000632?via%3Dihub
UR  - http://hdl.handle.net/10044/1/97724
VL  - 30
ER  -
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