title: Crystal structures of the ligand-binding region of uPARAP: effect of calcium ion binding.
abstract: The proteins of the mannose receptor (MR) family share a common domain organization and have a broad range of biological functions. Urokinase plasminogen activator receptor-associated protein (uPARAP) (or Endo180) is a member of this family and plays an important role in extracellular matrix remodelling through interaction with its ligands, including collagens and urokinase plasminogen activator receptor (uPAR). We report the crystal structures of the first four domains of uPARAP (also named the ligand-binding region, LBR) at pH 7.4 in Ca(2+)-bound and Ca(2+)-free forms. The first domain (cysteine-rich or 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 (LLRs) of the C-type lectin-like domain (CTLD) 1 and 2 (the third and fourth domain) mediate the direct contacts between these domains. These LLRs undergo a Ca(2+)-dependent conformational change, and this is likely to be 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 MR family.
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China College of Bioscience and Biotechnology, Fuzhou University, Fuzhou 350108, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center (BRIC), DK-2200 Copenhagen, Denmark.
authors.forename: Henrik J
authors.initials: HJ
authors.lastname: Jürgensen
authors.affiliation: Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center (BRIC), DK-2200 Copenhagen, Denmark Proteases and Tissue Remodeling Section, NIDCR, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Engelholm
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou 350108, China.
authors.forename: Longguang
authors.initials: L
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China.
authors.forename: Zhipu
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Center (BRIC), DK-2200 Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Behrendt
authors.affiliation: State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China College of Chemistry and Chemical Engineering, Fuzhou University, Fuzhou 350108, China mhuang@fjirsm.ac.cn.
authors.forename: Mingdong
authors.initials: M
authors.lastname: Huang
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D037241:Mannose-Binding Lectins / Q000737:chemistry* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; C404106:MRC2 protein, human; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D002118:Calcium
keywords: C-type lectin-like domain; crystal structure; endocytic collagen receptor; ligand-binding region; long loop region; receptor structure–function; uPARAP/Endo180