Structure and Specificity in RAMP Co-Receptor Oligomerization During Early Cardiac Development

Extracellular signals are transmitted to cells through two classes of receptors: signaling receptors (such as receptor tyrosine kinases or G-protein coupled receptors) that directly bind ligand and transduce signals to intracellular domains, and co-receptors that bind ligand, but typically do not transduce signal directly. In the latter case, co-receptors exist either as integral membrane proteins or GPI-anchored proteins, and are thought to transduce their signal through association with one or more signaling receptors. Although in some instances, association of co-receptor and signaling receptor into a functional complex has been demonstrated, the types of associations and the mechanisms underlying each association remain largely unknown.

We are interested in studying the association of a class of membrane co-receptors, receptor activity modifying proteins (RAMPs), with the calcitonin-like receptor (CLR) during early heart development. Using a combined biophysical and computational approach, we identify a key, conserved interface common to all RAMP co-receptors and demonstrate the importance of this interface for oligomerization with CLR. In vivo studies using zebrafish confirm the importance of RAMP1 during heart development as well as the significance of the predicted interface in regulating heart tubule formation and multiple signaling events during cardiac development.