Inhibition of vascular endothelial growth factor cotranslational translocation by the cyclopeptolide CAM741.
The cyclopeptolide CAM741 inhibits cotranslational translocation of vascular cell adhesion molecule 1 (VCAM1), which is dependent on its signal peptide. We now describe the identification of the signal peptide of vascular endothelial growth factor (VEGF) as the second target of CAM741. The mechanism by which the compound inhibits translocation of VEGF is very similar or identical to that of VCAM1, although the signal peptides share no obvious sequence similarities. By mutagenesis of the VEGF signal peptide, two important regions, located in the N-terminal and hydrophobic segments, were identified as critical for compound sensitivity. CAM741 alters positioning of the VEGF signal peptide at the translocon, and increasing hydrophobicity in the h-region reduces compound sensitivity and causes a different, possibly more efficient, interaction with the translocon. Although CAM741 is effective against translocation of both VEGF and VCAM1, the derivative NFI028 is able to inhibit only VCAM1, suggesting that chemical derivatization can alter not only potency, but also the specificity of the compounds.
Harant
Hanna
H
Novartis Institutes for BioMedical Research, Vienna, Austria. hanna.harant@novartis.com
Wolff
Barbara
B
Schreiner
Erwin P
EP
Oberhauser
Berndt
B
Hofer
Lotte
L
Lettner
Nicole
N
Maier
Sabine
S
de Vries
Jan E
JE
Lindley
Ivan J
IJ
D000595:Amino Acid Sequence; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D021382:Protein Sorting Signals / Q000187:drug effects* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects* / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C502318:CAM741; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D021382:Protein Sorting Signals; D018160:Receptors, Cytoplasmic and Nuclear; D018000:Receptors, Peptide; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C066973:signal sequence receptor