PMID- 22285761
OWN - NLM
STAT- MEDLINE
DCOM- 20120612
LR  - 20211021
IS  - 1089-8638 (Electronic)
IS  - 0022-2836 (Linking)
VI  - 416
IP  - 5
DP  - 2012 Mar 9
TI  - Crystal structure of the urokinase receptor in a ligand-free form.
PG  - 629-41
LID - 10.1016/j.jmb.2011.12.058 [doi]
AB  - The urokinase receptor urokinase-type plasminogen activator receptor (uPAR) is a 
      surface receptor capable of not only focalizing urokinase-type plasminogen 
      activator (uPA)-mediated fibrinolysis to the pericellular micro-environment but 
      also promoting cell migration and chemotaxis. Consistent with this 
      multifunctional role, uPAR binds several extracellular ligands, including uPA and 
      vitronectin. Structural studies suggest that uPAR possesses structural 
      flexibility. It is, however, not clear whether this flexibility is an inherent 
      property of the uPAR structure per se or whether it is induced upon ligand 
      binding. The crystal structure of human uPAR in its ligand-free state would 
      clarify this issue, but such information remains unfortunately elusive. We now 
      report the crystal structures of a stabilized, human uPAR (H47C/N259C) in its 
      ligand-free form to 2.4 A and in complex with amino-terminal fragment (ATF) to 
      3.2 A. The structure of uPAR(H47C/N259C) in complex with ATF resembles the 
      wild-type uPAR.ATF complex, demonstrating that these mutations do not perturb the 
      uPA binding properties of uPAR. The present structure of uPAR(H47C/N259C) 
      provides the first structural definition of uPAR in its ligand-free form, which 
      represents one of the biologically active conformations of uPAR as defined by 
      extensive biochemical studies. The domain boundary between uPAR DI-DII domains is 
      more flexible than the DII-DIII domain boundary. Two important structural 
      features are highlighted by the present uPAR structure. First, the DI-DIII domain 
      boundary may face the cell membrane. Second, loop 130-140 of uPAR plays a dynamic 
      role during ligand loading/unloading. Together, these studies provide new 
      insights into uPAR structure-function relationships, emphasizing the importance 
      of the inter-domain dynamics of this modular receptor.
CI  - Copyright A(c) 2012 Elsevier Ltd. All rights reserved.
FAU - Xu, Xiang
AU  - Xu X
AD  - Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, 
      USA.
FAU - Gardsvoll, Henrik
AU  - Gardsvoll H
FAU - Yuan, Cai
AU  - Yuan C
FAU - Lin, Lin
AU  - Lin L
FAU - Ploug, Michael
AU  - Ploug M
FAU - Huang, Mingdong
AU  - Huang M
LA  - eng
SI  - PDB/3U73
SI  - PDB/3U74
GR  - R01 HL086584/HL/NHLBI NIH HHS/United States
GR  - HL086584/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120121
PL  - Netherlands
TA  - J Mol Biol
JT  - Journal of molecular biology
JID - 2985088R
RN  - 0 (Ligands)
RN  - 0 (MRC2 protein, human)
RN  - 0 (Mannose-Binding Lectins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Vitronectin)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
EIN - J Mol Biol. 2012 Sep 7;422(1):158
MH  - Binding Sites
MH  - Cell Membrane/metabolism
MH  - Crystallization
MH  - Crystallography, X-Ray
MH  - Humans
MH  - Ligands
MH  - Mannose-Binding Lectins/*chemistry/genetics/metabolism
MH  - Membrane Glycoproteins/*chemistry/genetics/metabolism
MH  - Models, Molecular
MH  - Mutation
MH  - Protein Binding
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Receptors, Cell Surface/*chemistry/genetics/metabolism
MH  - Recombinant Proteins/chemistry/genetics/metabolism
MH  - Structure-Activity Relationship
MH  - Urokinase-Type Plasminogen Activator/metabolism
MH  - Vitronectin/metabolism
EDAT- 2012/01/31 06:00
MHDA- 2012/06/13 06:00
CRDT- 2012/01/31 06:00
PHST- 2011/10/30 00:00 [received]
PHST- 2011/12/23 00:00 [revised]
PHST- 2011/12/28 00:00 [accepted]
PHST- 2012/01/31 06:00 [entrez]
PHST- 2012/01/31 06:00 [pubmed]
PHST- 2012/06/13 06:00 [medline]
AID - S0022-2836(12)00002-2 [pii]
AID - 10.1016/j.jmb.2011.12.058 [doi]
PST - ppublish
SO  - J Mol Biol. 2012 Mar 9;416(5):629-41. doi: 10.1016/j.jmb.2011.12.058. Epub 2012 
      Jan 21.