Molecular modeling of protein-glycosaminoglycan interactions.
Forty-nine regions in 21 proteins were identified as potential heparin-binding sites based on the sequence organizations of their basic and nonbasic residues. Twelve known heparin-binding sequences in vitronectin, apolipoproteins E and B-100, and platelet factor 4 were used to formulate two search strings for identifying potential heparin-binding regions in other proteins. Consensus sequences for glycosaminoglycan recognition were determined as [-X-B-B-X-B-X-] and [-X-B-B-B-X-X-B-X-] where B is the probability of a basic residue and X is a hydropathic residue. Predictions were then made as to the heparin-binding domains in endothelial cell growth factor, purpurin, and antithrombin-III. Many of the natural sequences conforming to these consensus motifs show prominent amphipathic periodicities having both alpha-helical and beta-strand conformations as determined by predictive algorithms and circular dichroism studies. The heparin-binding domain of vitronectin was modeled and formed a hydrophilic pocket that wrapped around and folded over a heparin octasaccharide, yielding a complementary structure. We suggest that these consensus sequence elements form potential nucleation sites for the recognition of polyanions in proteins and may provide a useful guide in identifying heparin-binding regions in other proteins. The possible relevance of protein-glycosaminoglycans interactions in atherosclerosis is discussed.
Cardin
A D
AD
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Weintraub
H J
HJ
D000465:Algorithms; D000595:Amino Acid Sequence; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001665:Binding Sites; D002942:Circular Dichroism; D006023:Glycoproteins / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010978:Platelet Factor 4; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D019096:Vitronectin
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D006023:Glycoproteins; D006025:Glycosaminoglycans; D011506:Proteins; D019096:Vitronectin; D010978:Platelet Factor 4; D006493:Heparin