Crystal structures of the ligand binding region of uPARAP: effect of calcium ion binding

The proteins of the mannose receptor family share a common domain organization and have a broad range of biological functions. uPARAP (or Endo180) is a member of this family and plays an important role in extracellular matrix remodeling through interaction with its ligands, including collagens and uPAR. We report here the crystal structures of the first four domains of uPARAP (also named the ligand binding region, uPARAP-LBR) at pH 7.4 in Ca(2+)-bound and Ca(2+)-free forms. The first domain (CysR domain) folds into a new and unique conformation different from the β-trefoil fold of typical CysR domains. The so-called long loop regions of the C-type lectin like domain (CTLD) 1 and 2 (the third and fourth domain) mediate the direct contacts between these domains. These long loop regions undergo a Ca(2+) dependent conformational change, and this is likely the key structural determinant affecting the overall conformation of uPARAP. Our results provide a molecular mechanism to support the structural flexibility of uPARAP, and shed light on the structural flexibility of other members of the mannose receptor family.