Insights into Collagen Uptake by C-type Mannose Receptors from the Crystal Structure of Endo180 Domains 1-4.
The 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.
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Patricia
P
Paracuellos
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
David C
DC
Briggs
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Federico
F
Carafoli
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
Tan
T
Lončar
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK. Electronic address: e.hohenester@imperial.ac.uk.
Erhard
E
Hohenester
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D037181:Lectins, C-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011975:Receptors, Mitogen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
C408294:Endo180; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011975:Receptors, Mitogen; D003094:Collagen; D002118:Calcium