Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 24, Pages 10860-10865Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1004148107
Keywords
cell-cell attraction and repulsion; Eph receptor clustering
Categories
Funding
- National Institutes of Health [NS38486, GM75886]
- National Health and Medical Research Council [487922]
- National Center for Research Resources at the National Institutes of Health [RR-15301]
- United States Department of Energy [DE-AC02-06CH11357]
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- Merck Co., Inc.
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Eph receptor tyrosine kinases and their ephrin ligands regulate cell navigation during normal and oncogenic development. Signaling of Ephs is initiated in a multistep process leading to the assembly of higher-order signaling clusters that set off bidirectional signaling in interacting cells. However, the structural and mechanistic details of this assembly remained undefined. Here we present high-resolution structures of the complete EphA2 ectodomain and complexes with ephrin-A1 and A5 as the base unit of an Eph cluster. The structures reveal an elongated architecture with novel Eph/Eph interactions, both within and outside of the Eph ligand-binding domain, that suggest the molecular mechanism underlying Eph/ephrin clustering. Structure-function analysis, by using site-directed mutagenesis and cell-based signaling assays, confirms the importance of the identified oligomerization interfaces for Eph clustering.
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