TY - JOUR
T1 - Structure of the Repulsive Guidance Molecule (RGM)-neogenin signaling hub
AU - Bell, Christian H.
AU - Healey, Eleanor
AU - Van Erp, Susan
AU - Bishop, Benjamin
AU - Tang, Chenxiang
AU - Gilbert, Robert J.C.
AU - Radu Aricescu, A.
AU - Jeroen Pasterkamp, R.
AU - Siebold, Christian
PY - 2013/1/1
Y1 - 2013/1/1
N2 - Repulsive guidance molecule family members (RGMs) control fundamental and diverse cellular processes, including motility and adhesion, immune cell regulation, and systemic iron metabolism. However, it is not known how RGMs initiate signaling through their common cell-surface receptor, neogenin (NEO1). Here, we present crystal structures of the NEO1 RGM-binding region and its complex with human RGMB (also called dragon). The RGMB structure reveals a previously unknown protein fold and a functionally important autocatalytic cleavage mechanism and provides a framework to explain numerous disease-linked mutations in RGMs. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner. We demonstrate that all RGM-NEO1 complexes share this architecture, which therefore represents the core of multiple signaling pathways.
AB - Repulsive guidance molecule family members (RGMs) control fundamental and diverse cellular processes, including motility and adhesion, immune cell regulation, and systemic iron metabolism. However, it is not known how RGMs initiate signaling through their common cell-surface receptor, neogenin (NEO1). Here, we present crystal structures of the NEO1 RGM-binding region and its complex with human RGMB (also called dragon). The RGMB structure reveals a previously unknown protein fold and a functionally important autocatalytic cleavage mechanism and provides a framework to explain numerous disease-linked mutations in RGMs. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner. We demonstrate that all RGM-NEO1 complexes share this architecture, which therefore represents the core of multiple signaling pathways.
UR - http://www.scopus.com/inward/record.url?scp=84879793105&partnerID=8YFLogxK
U2 - 10.1126/science.1232322
DO - 10.1126/science.1232322
M3 - Article
AN - SCOPUS:84879793105
SN - 0036-8075
VL - 341
SP - 77
EP - 80
JO - Science
JF - Science
IS - 6141
ER -