8J1I

Crystal Structure of EphA8/SASH1 Complex

Summary for 8J1I

• Entry DOI: 10.2210/pdb8j1i/pdb
• Descriptor: Ephrin type-A receptor 8, SAM and SH3 domain-containing protein 1 (3 entities in total)
• Functional Keywords: complex, sam-sam, epha8 receptor, sash1, signaling protein
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 2
• Total formula weight: 15987.05

Authors

Liu, W.,Li, J.,Ding, Y. (deposition date: 2023-04-12, release date: 2024-02-28, Last modification date: 2024-09-11)

Primary citation

Ding, Y.,Chen, Q.,Shan, H.,Liu, J.,Lv, C.,Wang, Y.,Yuan, L.,Chen, Y.,Wang, Z.,Yin, Y.,Xiao, K.,Li, J.,Liu, W.
SASH1: A Novel Eph Receptor Partner and Insights into SAM-SAM Interactions.
J.Mol.Biol., 435:168243-168243, 2023

PubMed Abstract: The Eph (erythropoietin-producing human hepatocellular) receptor family, the largest subclass of receptor tyrosine kinases (RTKs), plays essential roles in embryonic development and neurogenesis. The intracellular Sterile Alpha Motif (SAM) domain presents a critical structural feature that distinguishes Eph receptors from other RTKs and participates in recruiting and binding downstream molecules. This study identified SASH1 (SAM and SH3 domain containing 1) as a novel Eph receptor-binding partner through SAM-SAM domain interactions. Our comprehensive biochemical analyses revealed that SASH1 selectively interacts with Eph receptors via its SAM1 domain, displaying the highest affinity for EphA8. The high-resolution crystal structure of the EphA8-SASH1 complex provided insights into the specific intermolecular interactions between these proteins. Cellular assays confirmed that EphA8 and SASH1 co-localize and co-precipitate in mammalian cells, with cancer mutations (EphA8 R942H or G978D) impairing this interaction. We demonstrated that SAM-SAM interaction is critical for SASH1-mediated regulation of EphA8 kinase activity, shedding new light on the Eph signaling pathway and expanding our understanding of the molecular basis of the tumor suppressor gene SASH1.

PubMed: 37619706
DOI: 10.1016/j.jmb.2023.168243

Experimental method

X-RAY DIFFRACTION (1.6 Å)