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

TY - JOUR

T1 - Crystal structures of the ligand-binding region of uPARAP

T2 - effect of calcium ion binding

AU - Yuan, Cai

AU - Jürgensen, Henrik J

AU - Engelholm, Lars H

AU - Li, Rui

AU - Liu, Min

AU - Jiang, Longguang

AU - Luo, Zhipu

AU - Behrendt, Niels

AU - Huang, Mingdong

N1 - © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1042/BCJ20160276

DO - 10.1042/BCJ20160276

M3 - Journal article

C2 - 27247422

SN - 0264-6021

VL - 473

SP - 2359

EP - 2368

JO - Biochemical Journal

JF - Biochemical Journal

IS - 15

ER -