TERTIARY STRUCTURES OF ACTIVIN AND ACTIVIN RECEPTORS

Salk Institute For Biological Studies, La Jolla CA

Investigators

Linked publications & trials

Abstract

The goal of the proposed study is to understand how biological signal is transduced across the membrane of a variety of target cells. Neuroendocrine peptides, activins exert a wide range of biological functions, which provides an excellent system to study such mechanisms. Two types of receptors are involved to trigger the signaling cascade upon their sequential binding to activin ligand. These are transmembrane proteins each with a single transmembrane helix and a cytoplasmic Ser/Thr kinase domain. Our goal is to have a structural understanding of how the binding of activin to the extracellular domain of the first receptor (type II activin receptor, ActRII) is then transduced to the downstream components of the signaling pathway to activate the kinase activity of the type I receptor (ActRII), which complexes with activin/ActRII complex. Our primary focus is on the structure determination of the extracellular, ligand-binding domain of ActRII (ActRII-ECD) in complex with either activin ligand, or ActRII-ECD, or both. We have currently obtained single crystals of ActRII-ECD in complex with activin ligand. We have also established high-level expression of ActRII-ECD to obtain single crystals. Based on stoichiometric ratios and binding affinity of different ligand/receptor complexes, in which either a heterodimeric (asymmetric) or homodimeric (symmetric) ligands, such as inhibin or activin, respectively, interacts with oligomeric complexes of two different types of receptor (asymmetric), we will establish the thermodynamic and kinetic rates of the processes. Expanding on our previous work on 1.5 A crystal structure of Act RII-ECD alone, we hope to provide a structural basis to correlate conformational changes induced upon complex formation between the ligand and receptor components to the transmembrane signaling mechanism. Recombinant forms of activins, inhibins (activin antagonist), ActRII-ECD are now available in large enough quantities to carry out chemical characterization and crystal structure determination of various complexes. Results will provide a firm basis to characterize the binding specificity of this ubiquitous neuropeptide, from which we can facilitate the design of effective and long-lasting peptidomimetic drugs to be used in modulating various hormone-related diseases and in population control.