1H NMR structural characterization of a nonmitogenic, vasodilatory, ischemia-protector and neuromodulatory acidic fibroblast growth factor.
A shortened genetically engineered form of acidic fibroblast growth factor (aFGF), that includes amino acids 28-154 of the full-length sequence (154 residues) plus Met in substitution of Leu27, does not induce cell division even though it is recognized by the cell membrane receptor, triggers the early mitogenic events, and retains the neuromodulatory, vasoactive, and cardio- and neuroprotective properties of the native full-length molecule. Taken together, these properties make this truncated aFGF a promising compound in the treatment of a wide assortment of neurological and cardiovascular pathologies where aFGF mitogenic activity is dispensable. Differences in biological activities between the shortened aFGF and the wild-type form have been attributed to lack of stability, and to the specific amino acid sequence missing at the N-terminus. Here we show that this shortened aFGF form has a three-dimensional structure even more stable than the wild-type protein at the mitogenic assay conditions; that this structure is similar to that of the wild type except at site 1 of interaction with the cell membrane receptor; that its lack of mitogenic activity cannot be attributed to the specific missing sequence; and that the vasodilatory activity of aFGF seems impaired by alterations of the three-dimensional structure of site 2 of interaction with the cell membrane receptor.
Lozano
R M
RM
Centro de Investigaciones Biológicas (CSIC), Velázquez 144, 28006 Madrid, Spain.
Pineda-Lucena
A
A
Gonzalez
C
C
Angeles Jiménez
M
M
Cuevas
P
P
Redondo-Horcajo
M
M
Sanz
J M
JM
Rico
M
M
Giménez-Gallego
G
G
D000595:Amino Acid Sequence; D000818:Animals; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry* / Q000494:pharmacology; D007511:Ischemia / Q000517:prevention & control; D009682:Magnetic Resonance Spectroscopy; D008934:Mitogens / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology
D008934:Mitogens; D018377:Neurotransmitter Agents; D014665:Vasodilator Agents; D016220:Fibroblast Growth Factor 1