期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2117675119
关键词
fibrin; structure-function; mechanochemistry; extracellular matrix
资金
- Alexander von Humboldt Foundation
- Science & Engineering Research Board [SERB-SRG/2021/001886]
- Welch Foundation [F-2008-20190330]
- Texas 4000 funding
- Human Frontiers in Science Program [RGP0045/2018]
- National Science Foundation [2046148, 2105175]
This study reveals that mechanical strain-induced structural changes in fibrin affect its biochemistry. Tensile deformation leads to molecular structural transitions of fibrin, reducing the binding ability of tissue plasminogen activator (tPA) and suppressing the biological activity of platelets on mechanically strained fibrin.
Fibrin is the fibrous protein network that comprises blood clots; it is uniquely capable of bearing very large tensile strains (up to 200%) due to multiscale force accommodation mechanisms. Fibrin is also a biochemical scaffold for numerous enzymes and blood factors. The biomechanics and biochemistry of fibrin have been independently studied. However, comparatively little is known about how fibrin biomechanics and biochemistry are coupled: how does fibrin deformation influence its biochemistry? In this study, we show that mechanically induced protein structural changes in fibrin affect fibrin biochemistry. We find that tensile deformation of fibrin leads to molecular structural transitions of a-helices to beta-sheets, which reduced binding of tissue plasminogen activator (tPA), an enzyme that initiates fibrin lysis. Moreover, binding of tPA and Thioflavin T, a commonly used beta-sheet marker, were mutually exclusive, further demonstrating the mechano-chemical control of fibrin biochemistry. Finally, we demonstrate that structural changes in fibrin suppressed the biological activity of platelets on mechanically strained fibrin due to reduced aIIb beta 3 integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and biological activity in an elegant mechanochemical feedback loop, which possibly extends to other fibrous biopolymers.
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