Abstract

Interactions between glycosaminoglycans (GAGs), e.g. heparan sulfate, chondroitin sulfate, etc. and proteins are fundamental aspects of the extracellular matrix. Earlier models based on primary sequences of amino acids have successfully predicted some protein-GAG interactions, but models of the complex, folded three dimensional protein structures provide the opportunity for unexpected or unexplained interactions. Collagen XI has been shown to be a critical component in collagen fibril formation. It also contains four putative heparin-binding sites; one in the TSPN-like amino terminal domain, one in a region that is present only in certain isoforms, and two on the major triple helical domain. It is hypothesized that these putative binding sites mediate interactions between collagen XI-coated fibrils and the surrounding GAGs and contribute to the control of collagen fibril development. In order to move toward a process for three dimensional modeling of GAG-protein interactions and to better understand collagen XI interactions with the surrounding extracellular matrix, we have modeled, using Modeller v8.1 and various web-based threading and ab initio servers, each of the four putative heparin-binding domains. We utilized protein-ligand docking algorithms (e.g. Autodock) to determine the relative interaction energy and conformation between each putative binding site and a heparin molecule. The computational results were compared to in vitro binding data.

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