Abstract
Decorin is the archetypal small leucine rich repeat proteoglycan of the vertebrate extracellular matrix (ECM). With its glycosaminoglycuronan chain, it is responsible for stabilizing inter-fibrillar organization. Type I collagen is the predominant member of the fibrillar collagen family, fulfilling both organizational and structural roles in animal ECMs. In this study, interactions between decoron (the decorin core protein) and binding sites in the d and e1 bands of the type I collagen fibril were investigated through molecular modeling of their respective X-ray diffraction structures. Previously, it was proposed that a model-based, highly curved concave decoron interacts with a single collagen molecule, which would form extensive van der Waals contacts and give rise to strong non-specific binding. However, the large well-ordered aggregate that is the collagen fibril places significant restraints on modes of ligand binding and necessitates multi-collagen molecular contacts. We present here a relatively high-resolution model of the decoron-fibril collagen complex. We find that the respective crystal structures complement each other well, although it is the monomeric form of decoron that shows the most appropriate shape complementarity with the fibril surface and favorable calculated energies of interaction. One molecule of decoron interacts with four to six collagen molecules, and the binding specificity relies on a large number of hydrogen bonds and electrostatic interactions, primarily with the collagen motifs KXGDRGE and AKGDRGE (d and e1 bands). This work helps us to understand collagen-decorin interactions and the molecular architecture of the fibrillar ECM in health and disease.
Highlights
Shape is arguably one of the most important issues in biology
We investigated the electrostatic landscape of the decoroncollagen fibril interaction under various modes of ligation, whilst taking into account spatial and steric considerations required of this complex
These included: the decoron monomer to collagen monomer and the decoron-dimer to collagen monomer and microfibril and fibrillar surface conformations in the two orientations (Dec NRC and Dec CRN, see methods and Figures 1–3) that the concave surface of the decoron molecule allows. We studied these in the context of the proposed decoronbinding sequence GAKGDRGETGP of the e1-microscopy band and the virtually identical GKNGDRGEPGP d-microscopy band sequence located approximately 0.13D apart within the gap region of the collagen fibril D-period (Figure 1)
Summary
Shape is arguably one of the most important issues in biology. Permanent and reproducible but not necessarily rigid molecularscale shapes provide the framework in which nervous, circulatory and digestive systems develop, and undergo changes in molecular pathology [1]. The shape and organization of each ECM depends on its collagen content and architecture, other ECM components, and cells being in the right place at the right time. Cells decide where they go, but maintaining their position is an extracellular process and, in an apparent paradox, the particular ECM arrangement helps cells decide what cell type they should be [2,3,4]. The mutual orientation and separation of these collagen fibrils is, in part, determined by proteoglycans (PGs) in the form of interfibrillar bridges [5], even in animals as distant from mammals as the echinoderms [6]. These bridges are soluble, but can be seen by staining with the electron dense marker Cupromeronic Blue that is visible in electron microscopy [5,7]
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