Abstract
SummaryThe C-type mannose receptor and its homolog Endo180 (or uPARAP, for urokinase plasminogen activator receptor-associated protein) mediate the endocytic uptake of collagen by macrophages and fibroblasts. This process is required for normal tissue remodeling, but also facilitates the growth and dissemination of tumors. We have determined the crystal structure at 2.5 Å resolution of the N-terminal region of Endo180, consisting of a ricin-like domain, a fibronectin type II (FN2) domain, and two C-type lectin (CTL) domains. The L-shaped arrangement of these domains creates a shallow trench spanning the FN2 and CTL1 domains, which was shown by mutagenesis to bind triple-helical and denatured collagen. Small-angle X-ray scattering showed that the L-shaped structure is maintained in solution at neutral and acidic pH, irrespective of calcium ion loading. Collagen binding was equally unaffected by acidic pH, suggesting that collagen release in endosomes is not regulated by changes within the Endo180 N-terminal region.
Highlights
Collagens are a major component of extracellular matrix and are essential for tissue stability
The structural basis for this activity, which is not shared by Endo180 (East et al, 2002), has been revealed by X-ray crystallography (Liu et al, 2000)
The critical FN2 domain is revealed to be integrated into a seemingly rigid L-shaped structure that allows the adjacent CTL1 domain to participate in collagen binding
Summary
Collagens are a major component of extracellular matrix and are essential for tissue stability. Fibrillar collagens, such as type I collagen, are found in interstitial matrices and form highly ordered suprastructures in the cornea, skin, tendon, and bone. Collagenolytic matrix metalloproteinases (MMPs) initially cleave fibrillar collagens at a single site three-quarters from the N terminus of the triple helix (Fields, 2013). The triple helices of the resulting fragments unfold at body temperature (Danielsen, 1987; Gross and Nagai, 1965), and the denatured collagen fragments are further degraded by a variety of extracellular proteinases or internalized by macrophages and fibroblasts for lysosomal degradation (Everts et al, 1996; Madsen et al, 2011)
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