Molecular modeling of protein-glycosaminoglycan interactions.

TLDR

Forty‑nine potential heparin‑binding sites were identified in 21 proteins based on their basic/nonbasic residue patterns, and the relevance of protein‑glycosaminoglycan interactions to atherosclerosis is discussed. The authors propose that the derived consensus sequence elements serve as nucleation sites for polyanion recognition in proteins and can guide the identification of heparin‑binding regions in other proteins. By applying two consensus search strings ([-X‑B‑B‑X‑B‑X‑] and [-X‑B‑B‑B‑X‑X‑B‑X‑]) derived from twelve known heparin‑binding sequences, the study predicted heparin‑binding domains in endothelial cell growth factor, purpurin, and antithrombin‑III. Natural sequences matching the consensus motifs display amphipathic periodicities of alpha‑helical and beta‑strand conformations, and modeling of vitronectin’s heparin‑binding domain revealed a hydrophilic pocket that wraps around a heparin octasaccharide.

Abstract

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.