Mechanisms of antithrombin polymerisation and heparin activation probed by the insertion of synthetic reactive loop peptides.
Incubation of antithrombin with a series of synthetic reactive loop peptides showed that 6-mer and 7-mer peptides, P14-P9 and P14-P8 of antithrombin respectively, induced loop-sheet polymerisation and binary complex formation. These peptides are likely to anneal to the upper part of the dominant A-sheet, favouring sheet opening and allowing insertion of a second reactive loop in the lower part of the A-sheet to form polymers. The insertion of longer peptides filled the A-sheet beyond the P7 position and prevented polymerisation. Heparinised antithrombin was more resistant to polymerisation and peptide insertion, indicating that heparin induces a conformational change that closes the A-sheet and expels the reactive loop.
Fitton
H L
HL
Department of Haematology, University of Cambridge, MRC Centre, UK.
Pike
R N
RN
Carrell
R W
RW
Chang
W S
WS
D000990:Antithrombin III / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D018257:Helix-Loop-Helix Motifs; D006493:Heparin / Q000737:chemistry*; D006358:Hot Temperature; D008970:Molecular Weight; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011108:Polymers; D011487:Protein Conformation; D015843:Serpins / Q000737:chemistry
D010455:Peptides; D011108:Polymers; D015843:Serpins; D000990:Antithrombin III; D006493:Heparin