Heparin-Protein Interactions

Abstract

Heparin, a sulfated polysaccharide belonging to the family of glycosaminoglycans, has numerous important biological activities, associated with its interaction with diverse proteins. Heparin is widely used as an anticoagulant drug based on its ability to accelerate the rate at which antithrombin inhibits serine proteases in the blood coagulation cascade. Heparin and the structurally related heparan sulfate are complex linear polymers comprised of a mixture of chains of different length, having variable sequences. Heparan sulfate is ubiquitously distributed on the surfaces of animal cells and in the extracellular matrix. It also mediates various physiologic and pathophysiologic processes. Difficulties in evaluating the role of heparin and heparan sulfate in vivo may be partly ascribed to ignorance of the detailed structure and sequence of these polysaccharides. In addition, the understanding of carbohydrate–protein interactions has lagged behind that of the more thoroughly studied protein–protein and protein–nucleic acid interactions. The recent extensive studies on the structural, kinetic, and thermodynamic aspects of the protein binding of heparin and heparan sulfate have led to an improved understanding of heparin–protein interactions. A high degree of specificity could be identified in many of these interactions. An understanding of these interactions at the molecular level is of fundamental importance in the design of new highly specific therapeutic agents. This review focuses on aspects of heparin structure and conformation, which are important for its interactions with proteins. It also describes the interaction of heparin and heparan sulfate with selected families of heparin‐binding proteins.

Role of Glycosaminoglycans in Cellular Communication

“…The high negative charge associated with GAGs facilitates their interaction with a large array of extracellular proteins. 6 The linear structures of GAGs restrict movement of bound proteins to one dimension in three-dimensional space, facilitating intercellular communication over these molecular wires. 7 The fast onrates and multivalency of protein-GAG binding make these interactions particularly important in dynamic systems.…”

“…As with other carbohydrates, the role of GAGs is primarily mediated through their interactions with proteins. 6 …”

Delineating mechanisms of dissociation for isomeric heparin disaccharides using isotope labeling and ion trap tandem mass spectrometry

“…The tandem mass spectrometry data presented herein also provide a foundation for further developments towards a practical analysis tool for the structural elucidation of larger, biologically important heparin/HS oligosaccharides by using mass spectrometry. H eparin and heparan sulfate (HS) glycosaminoglycans (GAGs) have been implicated in a host of biological functions including blood coagulation, inflammatory processes, cell-cell and cellmatrix interactions, as well as cell growth and differentiation [1]. Although heparin has been used clinically as an anticoagulant for decades, and the closely related species, heparan sulfate has been identified as a key player with many biological roles, the absolute structures responsible for the various attributed functions are complex and have only recently been deciphered in a few specific cases.…”

“…Heparin/HS polysaccharides consist of a repeating disaccharide unit of [HexA␤ (1,4)GlcN␣ (1,4)] n . The hexuronic acid (HexA) residue can be either L-iduronic acid (IdoA) or D-glucuronic acid (GlcA) depending on the stereochemistry of the C5 carboxylic acid group, and may be sulfated at the C2 position.…”

Old and new applications of non-anticoagulant heparin

“…Heparin and LMWHs are widely used for the prevention and treatment of thrombotic events by inhibiting antithrombin III (AT) and factor Xa through a specific oligosaccharide binding sequence (ATBR) present in only one third of unfractionated heparin chains as has been well-documented in two recent reviews [1,2]. Heparin, the most negatively charged biopolymer has an average of four negative charges for each disaccharide unit, can interact with a wide range of proteins, with interactions that exhibit a range of specificities [3] and induce several associated biological activities. These involve plasma or tissue proteins such as heparin cofactor II (HCII), tissue factor plasminogen inhibitor (TFPI), lipoproteinlipase, growth factors and heparanase.…”