Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR.

Cell Reports
Wupeng YanDhirendra K Simanshu

Abstract

Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. SPRED1 and NF1 loss-of-function mutations occur across multiple cancer types and developmental diseases. Analysis of the neurofibromin-SPRED1 interface provides a rationale for mutations observed in Legius syndrome and suggests why SPRED1 can bind to neurofibromin but no other RasGAPs. We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions.

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Citations

Nov 12, 2020·Biomolecules·Daniel Abankwa, Alemayehu A Gorfe
Oct 31, 2020·Cells·Mohammed BergougHélène Bénédetti
Dec 12, 2020·The Journal of Experimental Medicine·Julien AblainLeonard I Zon
Dec 18, 2020·Human Molecular Genetics·Yan CuiHelen Morrison
Feb 6, 2021·Biochemical Society Transactions·Rohan Chippalkatti, Daniel Abankwa
Oct 25, 2020·Cancers·Arianna Bellazzo, Licio Collavin
Jan 22, 2021·Archives of Biochemistry and Biophysics·José L NeiraAdrián Velázquez-Campoy
Apr 20, 2021·Genes & Development·Claire Lorenzo, Frank McCormick
Jun 10, 2021·Communications Biology·Silke PudewellMohammad R Ahmadian
Jun 15, 2021·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Akihiko YoshimuraMinako Ito
Oct 10, 2021·American Journal of Human Genetics·Marialetizia MottaMarco Tartaglia

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Methods Mentioned

BETA
GTPase
isothermal titration calorimetry
GTPases
NMR
two-hybrid
protein folding
immunoprecipitation
flow cytometry
X-ray
Destination

Software Mentioned

refine
MicroCal PEAQ - ITC
Phaser
PyMOL
GraphPad Prism
Phenix
CCP4
COOT
XDS
ESI

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