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Structural and functional consequences of methionine oxidation in thrombomodulin
Matthew J Wood1, Judith Helena Prieto, Elizabeth A Komives
1Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-5430, USA.
Biochimica Et Biophysica Acta
|February 1, 2005
Summary
Oxidation of methionine 388 in thrombomodulin (TM) disrupts its structure and anticoagulant function. This molecular change is linked to increased thrombotic risk and reduced protein C activation.
Area of Science:
- Biochemistry
- Molecular Biology
- Hematology
Background:
- Thrombomodulin (TM) is a crucial endothelial glycoprotein regulating thrombin activity.
- TM switches thrombin from pro-coagulant to anticoagulant functions, primarily via protein C activation.
- The anticoagulant activity resides in the fourth and fifth EGF-like domains of TM.
Purpose of the Study:
- To investigate the structural and functional impact of Met 388 oxidation in TM.
- To elucidate the role of Met 388 in maintaining the interdomain linkage and TM activity.
- To understand the implications of TM oxidation in thrombotic conditions.
Main Methods:
- X-ray crystallography and Nuclear Magnetic Resonance (NMR) spectroscopy were employed.
- Structural and dynamic analyses were performed on wild-type and variant TM at position 388.
- Functional assays assessed the anticoagulant activity of oxidized TM.
Main Results:
- Met 388 forms a critical linkage between the fourth and fifth EGF-like domains of TM.
- Oxidation of Met 388 alters the structure of the fifth domain and disrupts interdomain contacts.
- Oxidized TM exhibits reduced anticoagulant activity and impaired protein C activation.
Conclusions:
- Met 388 oxidation subtly but critically alters TM structure and function.
- Oxidative stress leading to Met 388 oxidation may contribute to a higher thrombotic tendency.
- Understanding TM oxidation is vital for comprehending thrombosis and developing therapeutic strategies.