Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM domain interactions

ELife
Yue WangMingjie Zhang

Abstract

The Eph receptor tyrosine kinase (RTK) family is the largest subfamily of RTKs playing critical roles in many developmental processes such as tissue patterning, neurogenesis and neuronal circuit formation, angiogenesis, etc. How the 14 Eph proteins, via their highly similar cytoplasmic domains, can transmit diverse and sometimes opposite cellular signals upon engaging ephrins is a major unresolved question. Here, we systematically investigated the bindings of each SAM domain of Eph receptors to the SAM domains from SHIP2 and Odin, and uncover a highly specific SAM-SAM interaction-mediated cytoplasmic Eph-effector binding pattern. Comparative X-ray crystallographic studies of several SAM-SAM heterodimer complexes, together with biochemical and cell biology experiments, not only revealed the exquisite specificity code governing Eph/effector interactions but also allowed us to identify SAMD5 as a new Eph binding partner. Finally, these Eph/effector SAM heterodimer structures can explain many Eph SAM mutations identified in patients suffering from cancers and other diseases.

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Citations

Feb 16, 2019·Current Protein & Peptide Science·Marian VincenziMarilisa Leone
Sep 21, 2019·Chembiochem : a European Journal of Chemical Biology·Flavia A MercurioMarilisa Leone
Oct 8, 2019·Molecular Biology and Evolution·Aida ArcasM Ángela Nieto
Oct 12, 2018·Current Medicinal Chemistry·Marian VincenziMarilisa Leone
Jun 5, 2020·Pharmaceuticals·Robert M Hughes, Jitka A I Virag
Apr 4, 2020·The Journal of Biological Chemistry·Suhita RayKyle J Hewitt

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Methods Mentioned

BETA
gel-filtration
gel filtration
ubiquitination
X-ray
NMR
pull-down
PCR
size-exclusion chromatography
pulldown
Transfection

Software Mentioned

PyMOL
Origin
Coot
PHENIX
MolProbity
Refmac5
ImageJ
GraphPad Prism
HKL2000
PHASER

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