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Protein Sci. 2018 Mar;27(3):714-724. doi: 10.1002/pro.3366. Epub 2017 Dec 28.

Computational predictions of cysteine cathepsin-mediated fibrinogen proteolysis.

Author information

1
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia.
2
School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, Georgia.

Abstract

Fibrin clot formation is a proteolytic cascade of events with thrombin and plasmin identified as the main proteases cleaving fibrinogen precursor, and the fibrin polymer, respectively. Other proteases may be involved directly in fibrin(ogen) cleavage, clot formation, and resolution, or in the degradation of fibrin-based scaffolds emerging as useful tools for tissue engineered constructs. Here, cysteine cathepsins are investigated for their putative ability to hydrolyze fibrinogen, since they are potent proteases, first identified in lysosomal protein degradation and known to participate in extracellular proteolysis. To further explore this, we used two independent computational technqiues, molecular docking and bioinformatics sequence analysis (PACMANS), to predict potential binding interactions and sites of hydrolysis between cathepsins K, L, and S and fibrinogen. By comparing the results from these two objective, computational methods, it was determined that cathepsins K, L, and S do bind and cleave fibrinogen α, β, and γ chains at similar and unique sites. These differences were visualized experimentally by the unique cleaved fibrinogen banding patterns after incubation with each of the cathepsins, separately. In conclusion, human cysteine cathepsins K, L, and S are a new class of proteases that should be considered during fibrin(ogen) degradation studies both for disease processes where coagulation is a concern, and also in the implementation and design of bioengineered systems.

KEYWORDS:

bioengineering; cathepsins; cysteine protease; extracellular matrix; fibrinogen; fibrinolysis; hydrolysis; molecular docking

PMID:
29266558
PMCID:
PMC5818743
DOI:
10.1002/pro.3366
[Indexed for MEDLINE]
Free PMC Article

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