Galectin-1(L11A) predicted from a computed galectin-1 farnesyl-binding pocket selectively inhibits Ras-GTP.
Ras biological activity necessitates membrane anchorage that depends on the Ras farnesyl moiety and is strengthened by Ras/galectin-1 interactions. We identified a hydrophobic pocket in galectin-1, analogous to the Cdc42 geranylgeranyl-binding cavity in RhoGDI, possessing homologous isoprenoid-binding residues, including the critical L11, whose RhoGDI L77 homologue changes dramatically on Cdc42 binding. By substituting L11A, we obtained a dominant interfering galectin-1 that possessed normal carbohydrate-binding capacity but inhibited H-Ras GTP-loading and extracellular signal-regulated kinase activation, dislodged H-Ras(G12V) from the cell membrane, and attenuated H-Ras(G12V) fibroblast transformation and PC12-cell neurite outgrowth. Thus, independently of carbohydrate binding, galectin-1 cooperates with Ras, whereas galectin-1(L11A) inhibits it.
Rotblat
Barak
B
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
Niv
Hagit
H
André
Sabine
S
Kaltner
Herbert
H
Gabius
Hans-Joachim
HJ
Kloog
Yoel
Y
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D037483:Galectin 1 / Q000737:chemistry* / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000737:chemistry / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020935:MAP Kinase Signaling System; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016716:PC12 Cells; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D051381:Rats; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
C569638:ARHGDIA protein, human; D037483:Galectin 1; D020730:Guanine Nucleotide Dissociation Inhibitors; D013729:Terpenes; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D006160:Guanosine Triphosphate; D020764:cdc42 GTP-Binding Protein; D018631:ras Proteins