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

Wupeng Yan1, Evan Markegard2, Srisathiyanarayanan Dharmaiah1

  • 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA.

Cell Reports
|July 23, 2020
PubMed

Insights

Sprouty-related, EVH1 domain-containing protein 1 (SPRED1) binds neurofibromin, regulating RAS/MAPK signaling. This interaction is disrupted by cancer-associated mutations and EGFR signaling, impacting cell growth.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • Sprouty-related, EVH1 domain-containing (SPRED) proteins are negative regulators of RAS/mitogen-activated protein kinase (MAPK) signaling.
  • SPRED1 is believed to inhibit RAS by recruiting neurofibromin, a Ras GTPase-activating protein (RasGAP), to the plasma membrane.

Purpose of the Study:

  • To elucidate the structural basis of the SPRED1-neurofibromin interaction and its role in RAS/MAPK pathway regulation.
  • To investigate the impact of mutations and oncogenic signaling on the SPRED1-neurofibromin complex and its function.

Main Methods:

  • X-ray crystallography to determine the structure of the neurofibromin GAP domain complexed with SPRED1 and KRAS.
  • Biochemical assays to analyze SPRED1-neurofibromin binding and RasGAP activity.
  • Cellular assays to assess the effect of oncogenic signaling on SPRED1 phosphorylation and complex stability.

Main Results:

  • The crystal structure reveals how SPRED1 targets neurofibromin to the membrane for simultaneous interaction with activated KRAS.
  • Analysis of the interface explains mutations in Legius syndrome and SPRED1's specificity for neurofibromin.
  • Oncogenic EGFR signaling phosphorylates SPRED1 at Serine 105, disrupting the SPRED1-neurofibromin complex.

Conclusions:

  • SPRED1 acts as a scaffold, recruiting neurofibromin to regulate active KRAS levels.
  • Dysregulation of the SPRED1-neurofibromin interaction contributes to pathologic conditions like cancer and developmental diseases.
  • Understanding this complex provides mechanistic insights into RAS/MAPK pathway control.
Keywords:
Legius syndromeRAS-RAF-ERK pathwayRASopathyRasGAPneurofibromatosis type 1

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