5mr5

Publication Abstract from PubMed

Neurturin (NRTN) provides trophic support to neurons and is considered a therapeutic agent for neurodegenerative diseases, such as Parkinson's disease. It binds to its co-receptor GFRa2 and the resulting NRTN:GFRa2 complex activates the transmembrane receptors RET or NCAM. We report the crystal structure of NRTN, alone and in complex with GFRa2. This is the first crystal structure of a GFRa with all three domains and shows that domain 1 does not interact directly with NRTN, but may support an interaction with RET and/or NCAM, via a highly conserved surface. In addition, biophysical results show that the relative concentration of GFRa2 on cell surfaces can affect the functional affinity of NRTN through avidity effects. We have identified a heparan sulfate binding site on NRTN and a putative binding site in GFRa2, suggesting that heparan sulfate has a role in assembly of the signalling complex. We further show that mutant NRTN with reduced affinity for heparan sulfate may provide a route forward for delivery of NRTN with increased exposure in preclinical in vivo models and ultimately to Parkinson's patients.

Structure and biophysical characterisation of the human full-length Neurturin-GFRa2 complex - a role for heparan sulfate in signalling.,Sandmark J, Dahl G, Oster L, Xu B, Johansson P, Akerud T, Aagaard A, Davidsson P, Bigalke JM, Sorhede-Winzell M, Rainey GJ, Roth RG J Biol Chem. 2018 Feb 2. pii: RA117.000820. doi: 10.1074/jbc.RA117.000820. PMID:29414779^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.