Processing of PDGF gene products determines interactions with glycosaminoglycans
✍ Scribed by Florentyna Lustig; Johan Hoebeke; Carolina Simonson; Gunnel Östergren-Lundén; Göran Bondjers; Ulla Rüetchi; Gunnar Fager
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 105 KB
- Volume
- 12
- Category
- Article
- ISSN
- 0952-3499
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✦ Synopsis
The platelet derived growth factor (PDGF), a mitogen for mesenchymal cells, may be bound to and inhibited by heparin and other glycosaminoglycans. PDGF is a homo-or heterodimer of A-and B-chains. They occur as short (A 109 and B 110 ) and long (A 125 and B 160 ) isoforms. The latter contain basic carboxyl-terminal extensions. Dimeric A 125 binds to heparin through its basic extension in a two-step reaction. The mechanism involves a conformational change and is consistent with a Monod-Wyman-Changeux allosteric model. Previous indirect experiments suggested that three critical amino acids (basic R 111 , K 116 and polar T 125 ) might be involved. Here, direct binding experiments using dimeric full-length mutants in surface plasmon resonanse analysis showed that all three critical amino acids in an R(X) 4 K(X) 8 T-motif contributed in a concerted manner to the high affinity binding. Mutations of these amino acids to alanine resulted in large thermodynamic changes, loss of the allosteric mechanism and order(s) of magnitude lower binding affinity. The binding mechanism and affinity of long dimeric rB were similar to the mutants. Short dimeric rA 109 and rB 110 showed 100 times lower binding affinity than rA 125 . Consequently, interactions with glycosaminoglycans in tissues varies between PDGF isoforms and may influence their local accumulation and activity.