PMID- 12881310
OWN - NLM
STAT- MEDLINE
DCOM- 20040105
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 102
IP  - 10
DP  - 2003 Nov 15
TI  - The kringle stabilizes urokinase binding to the urokinase receptor.
PG  - 3600-8
AB  - The structural basis of the interaction between single-chain urokinase-type 
      plasminogen activator (scuPA) and its receptor (uPAR) is incompletely defined. 
      Several observations indicated the kringle facilitates the binding of uPA to 
      uPAR. A scuPA variant lacking the kringle (Delta K-scuPA) bound to soluble uPAR 
      (suPAR) with the similar "on-rate" but with a faster "off-rate" than wild-type 
      (WT)-scuPA. Binding of Delta K-scuPA, but not WT-scuPA, to suPAR was comparably 
      inhibited by its growth factor domain (GFD) and amino-terminal fragment (ATF). 
      ATF and WT-scuPA, but not GFD, scuPA lacking the GFD (Delta GFD-scuPA), or Delta 
      K-scuPA reconstituted the isolated domains of uPAR. ATF completely inhibited the 
      enzymatic activity of WT-scuPA-suPAR unlike comparable concentrations of GFD. 
      Variants containing mutations that alter the charge, length, or flexibility of 
      linker sequence (residues 43-49) between the GFD and the kringle displayed a 
      lower affinity for uPAR, were unable to reconstitute uPAR domains, and their 
      binding to uPAR was inhibited by GFD in the same manner as Delta K-scuPA. A scuPA 
      variant in which the charged amino acids in the heparin binding site (HBS) in the 
      kringle domain were mutated to alanines behaved like Delta K-scuPA, indicating 
      that that the structure of the kringle as well as its interaction with the GFD 
      govern receptor binding. These data demonstrate an important role for the kringle 
      in stabilizing the binding of scuPA to uPAR.
FAU - Bdeir, Khalil
AU  - Bdeir K
AD  - Department of Pathology and Laboratory Medicine, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Kuo, Alice
AU  - Kuo A
FAU - Sachais, Bruce S
AU  - Sachais BS
FAU - Rux, Ann H
AU  - Rux AH
FAU - Bdeir, Yasmina
AU  - Bdeir Y
FAU - Mazar, Andrew
AU  - Mazar A
FAU - Higazi, Abd Al-Roof
AU  - Higazi AA
FAU - Cines, Douglas B
AU  - Cines DB
LA  - eng
GR  - HL60169/HL/NHLBI NIH HHS/United States
GR  - HL66442/HL/NHLBI NIH HHS/United States
GR  - HL67381/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030724
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (PLAUR protein, human)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Urokinase Plasminogen Activator)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Binding, Competitive
MH  - Genetic Variation
MH  - Humans
MH  - Kringles/genetics/*physiology
MH  - Mutation
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Receptors, Cell Surface/*metabolism
MH  - Receptors, Urokinase Plasminogen Activator
MH  - Surface Plasmon Resonance
MH  - Urokinase-Type Plasminogen Activator/genetics/*metabolism
EDAT- 2003/07/26 05:00
MHDA- 2004/01/06 05:00
CRDT- 2003/07/26 05:00
PHST- 2003/07/26 05:00 [pubmed]
PHST- 2004/01/06 05:00 [medline]
PHST- 2003/07/26 05:00 [entrez]
AID - S0006-4971(20)50360-1 [pii]
AID - 10.1182/blood-2003-03-0949 [doi]
PST - ppublish
SO  - Blood. 2003 Nov 15;102(10):3600-8. doi: 10.1182/blood-2003-03-0949. Epub 2003 Jul 
      24.