Structural studies of GDNF family ligands with their receptors-Insights into ligand recognition and activation of receptor tyrosine kinase RET

RET is the receptor for glial cell line-derived neurotrophic factor family of ligands (GFLs). It is different from most other members in the receptor tyrosine kinase (RTK) family with the requirement of a co-receptor, GFR alpha, for ligand recognition and activation. Through the common signal transducer RET, GFLs are crucial for the development and maintenance of distinct sets of central and peripheral neurons, which has led to a series of studies towards understanding the structure, function and signaling mechanisms of GFLs with GFR alpha and RET receptors. Here I summarize our current understanding of the molecular basis underlying ligand recognition and activation of RET, focusing on the interactions of GFLs with their respective GFR alpha receptors, the recently determined crystal structure of RET extracellular region and a proposed GFL-GFR alpha-RET ternary complex model based on extensive structural, biochemical and functional data. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases. (C) 2012 Elsevier B.V. All rights reserved.