Cyclophilin A (CyPA) induces chemotaxis independent of its peptidylprolyl cis-trans isomerase activity: direct binding between CyPA and the ectodomain of CD147.
Cyclophilin A (CyPA) is a ubiquitously distributed peptidylprolyl cis-trans isomerase (PPIase) that possesses diverse biological functions. Extracellular CyPA is a potent chemokine, which can directly induce leukocyte chemotaxis and contribute to the pathogenesis of inflammation-mediated diseases. Although it has been identified that the chemotaxis activity of CyPA is mediated through its cell surface signaling receptor CD147, the role of CyPA PPIase activity in this process is disputable, and the underlying molecular mechanism is still poorly understood. In this study, we present the first evidence that CyPA induces leukocyte chemotaxis through a direct binding with the ectodomain of CD147 (CD147(ECT)), independent of its PPIase activity. Although NMR study indicates that the CD147(ECT) binding site on CyPA overlaps with the PPIase active site, the PPIase inactive mutant CyPA(R55A) exhibits similar CD147(ECT) binding ability and chemotaxis activity to those of CyPA(WT). Furthermore, we have identified three key residues of CyPA involved in CD147(ECT) binding and found that mutations H70A, T107A, and R69A result in similar levels of reduction in CD147(ECT) binding ability and chemotaxis activity for CyPA, without affecting the PPIase activity. Our findings indicate that there exists a novel mechanism for CyPA to regulate cellular signaling processes, shedding new light on its applications in drug development and providing a new targeting site for drug design.
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and.
Fei
F
Song
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and.
Xin
X
Zhang
the Beijing Nuclear Magnetic Resonance Center,; College of Chemistry and Molecular Engineering, and.
Xiao-Bai
XB
Ren
the Department of Clinical Immunology, Xijing Hospital, the Fourth Military Medical University, 17 West Changle Road, Xi'an 710032 and.
Ping
P
Zhu
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and.
Jing
J
Xu
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and.
Li
L
Wang
the Beijing Nuclear Magnetic Resonance Center,; College of Life Science, Peking University, Beijing 100871, China.
Yi-Fei
YF
Li
the Beijing Nuclear Magnetic Resonance Center,; College of Chemistry and Molecular Engineering, and.
Nan
N
Zhong
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and.
Qiang
Q
Ru
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and.
Da-Wei
DW
Zhang
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and.
Jian-Li
JL
Jiang
the Beijing Nuclear Magnetic Resonance Center,; College of Chemistry and Molecular Engineering, and; College of Life Science, Peking University, Beijing 100871, China. Electronic address: binxia@pku.edu.cn.
Bin
B
Xia
From the Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology and. Electronic address: znchen@fmmu.edu.cn.
Zhi-Nan
ZN
Chen
D019943:Amino Acid Substitution; D051926:Basigin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002633:Chemotaxis / Q000502:physiology*; D021984:Cyclophilin A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D020125:Mutation, Missense; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding
C497886:BSG protein, human; D051926:Basigin; D021984:Cyclophilin A
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