6V6F

Crystal structure of Q61L KRAS(GMPPNP)-NF1(GRD)-SPRED1(EVH1) complex

6V6F の概要

• エントリーDOI: 10.2210/pdb6v6f/pdb
• 分子名称: Sprouty-related, EVH1 domain-containing protein 1, Neurofibromin, GTPase KRas, ... (8 entities in total)
• 機能のキーワード: neurofibromin, ras, legius syndrome, rasgap, gap, spred, k-ras, evh1, grd, oncoprotein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 70533.75

構造登録者

Yan, W.,Simanshu, D.K. (登録日: 2019-12-05, 公開日: 2020-07-15, 最終更新日: 2023-10-11)

主引用文献

Yan, W.,Markegard, E.,Dharmaiah, S.,Urisman, A.,Drew, M.,Esposito, D.,Scheffzek, K.,Nissley, D.V.,McCormick, F.,Simanshu, D.K.
Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR.
Cell Rep, 32:107909-107909, 2020

PubMed 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.

PubMed: 32697994
DOI: 10.1016/j.celrep.2020.107909

実験手法

X-RAY DIFFRACTION (2.542 Å)