TY - JOUR
T1 - Structural Basis of Interaction between Urokinase-type Plasminogen Activator and its Receptor
AU - Barinka, Cyril
AU - Parry, Graham
AU - Callahan, Jennifer
AU - Shaw, David E.
AU - Kuo, Alice
AU - Bdeir, Khalil
AU - Cines, Douglas B.
AU - Mazar, Andrew
AU - Lubkowski, Jacek
N1 - Funding Information:
We thank Dr Joseph Tropea and Mr Scott Cherry for help in preparation of the complex samples, Dr Zbigniew Dauter for his help with collection of X-ray data for the suPAR WT /ATF crystals, and Dr Peter Zwart for help with initial molecular replacement searches. Diffraction data were collected at the South-East Regional Collaborative Access Team (SER-CAT) beamline 22-ID, located at the Advanced Photon Source, Argonne National Laboratory. Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract no. W-31-109-Eng38. This project was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to J.L.), by grants HL60169, HL076206, CA83121, and HL76406, and a grant from the University of Pennsylvania Research Foundation (to D.B.C.).
PY - 2006/10/20
Y1 - 2006/10/20
N2 - Recent studies indicate that binding of the urokinase-type plasminogen activator (uPA) to its high-affinity receptor (uPAR) orchestrates uPAR interactions with other cellular components that play a pivotal role in diverse (patho-)physiological processes, including wound healing, angiogenesis, inflammation, and cancer metastasis. However, notwithstanding the wealth of biochemical data available describing the activities of uPAR, little is known about the exact mode of uPAR/uPA interactions or the presumed conformational changes that accompany uPA/uPAR engagement. Here, we report the crystal structure of soluble urokinase plasminogen activator receptor (suPAR), which contains the three domains of the wild-type receptor but lacks the cell-surface anchoring sequence, in complex with the amino-terminal fragment of urokinase-type plasminogen activator (ATF), at the resolution of 2.8 Å. We report the 1.9 Å crystal structure of free ATF. Our results provide a structural basis, represented by conformational changes induced in uPAR, for several published biochemical observations describing the nature of uPAR/uPA interactions and provide insight into mechanisms that may be responsible for the cellular responses induced by uPA binding.
AB - Recent studies indicate that binding of the urokinase-type plasminogen activator (uPA) to its high-affinity receptor (uPAR) orchestrates uPAR interactions with other cellular components that play a pivotal role in diverse (patho-)physiological processes, including wound healing, angiogenesis, inflammation, and cancer metastasis. However, notwithstanding the wealth of biochemical data available describing the activities of uPAR, little is known about the exact mode of uPAR/uPA interactions or the presumed conformational changes that accompany uPA/uPAR engagement. Here, we report the crystal structure of soluble urokinase plasminogen activator receptor (suPAR), which contains the three domains of the wild-type receptor but lacks the cell-surface anchoring sequence, in complex with the amino-terminal fragment of urokinase-type plasminogen activator (ATF), at the resolution of 2.8 Å. We report the 1.9 Å crystal structure of free ATF. Our results provide a structural basis, represented by conformational changes induced in uPAR, for several published biochemical observations describing the nature of uPAR/uPA interactions and provide insight into mechanisms that may be responsible for the cellular responses induced by uPA binding.
KW - X-ray crystallography
KW - kringle domain
KW - plasminogen
KW - protein/protein interactions
KW - urokinase receptor
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U2 - 10.1016/j.jmb.2006.08.063
DO - 10.1016/j.jmb.2006.08.063
M3 - Article
C2 - 16979660
AN - SCOPUS:33749159851
SN - 0022-2836
VL - 363
SP - 482
EP - 495
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 2
ER -
