6v65

From Proteopedia

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

Structural highlights

6v65 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.763Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SPRE1_HUMAN Legius syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

SPRE1_HUMAN Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase. Negatively regulates hematopoiesis of bone marrow (By similarity).

Publication Abstract from PubMed

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.

Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR.,Yan W, Markegard E, Dharmaiah S, Urisman A, Drew M, Esposito D, Scheffzek K, Nissley DV, McCormick F, Simanshu DK Cell Rep. 2020 Jul 21;32(3):107909. doi: 10.1016/j.celrep.2020.107909. PMID:32697994^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yan W, Markegard E, Dharmaiah S, Urisman A, Drew M, Esposito D, Scheffzek K, Nissley DV, McCormick F, Simanshu DK. Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR. Cell Rep. 2020 Jul 21;32(3):107909. PMID:32697994 doi:10.1016/j.celrep.2020.107909