The Function of Embryonic Stem Cell-expressed RAS (E-RAS), a Unique RAS Family Member, Correlates with Its Additional Motifs and Its Structural Properties.
E-RAS is a member of the RAS family specifically expressed in embryonic stem cells, gastric tumors, and hepatic stellate cells. Unlike classical RAS isoforms (H-, N-, and K-RAS4B), E-RAS has, in addition to striking and remarkable sequence deviations, an extended 38-amino acid-long unique N-terminal region with still unknown functions. We investigated the molecular mechanism of E-RAS regulation and function with respect to its sequence and structural features. We found that N-terminal extension of E-RAS is important for E-RAS signaling activity. E-RAS protein most remarkably revealed a different mode of effector interaction as compared with H-RAS, which correlates with deviations in the effector-binding site of E-RAS. Of all these residues, tryptophan 79 (arginine 41 in H-RAS), in the interswitch region, modulates the effector selectivity of RAS proteins from H-RAS to E-RAS features.
Institute of Biochemistry and Molecular Biology II, Hepatology, and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40255 Düsseldorf.
Saeideh
S
Nakhaei-Rad
Institute of Biochemistry and Molecular Biology II, Hepatology, and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40255 Düsseldorf.
Hossein
H
Nakhaeizadeh
Clinic of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40255 Düsseldorf.
Claus
C
Kordes
Institute of Biochemistry and Molecular Biology II, Hepatology, and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40255 Düsseldorf; Leibniz Institute for Age Research-Fritz Lipmann Institute, 07745 Jena.
Ion C
IC
Cirstea
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
Malte
M
Schmick
Institute of Biochemistry and Molecular Biology II, Hepatology, and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40255 Düsseldorf.
Radovan
R
Dvorsky
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.
Philippe I H
PIH
Bastiaens
Clinic of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40255 Düsseldorf.
Dieter
D
Häussinger
Institute of Biochemistry and Molecular Biology II, Hepatology, and Infectious Diseases, Medical Faculty of the Heinrich-Heine University, 40255 Düsseldorf. Electronic address: reza.ahmadian@uni-duesseldorf.de.
Mohammad Reza
MR
Ahmadian
D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004285:Dogs; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*
C474774:ERas protein, human; C501009:HRAS protein, human; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras)
E-RAS; H-RAS; RAS protein; Raf kinase; effector selection; embryonic stem cell-expressed RAS; phosphatidylinositide 3-kinase (PI 3-kinase); phosphatidylinositol kinase (PI kinase); small GTPase; specificity determining residues