Structural control of fibrin bioactivity by mechanical deformation.
Structural control of fibrin bioactivity by mechanical deformation.
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DOI：
10.1073/pnas.2117675119
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发表时间：
2022-05-31
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
纤维蛋白在生物学中扮演着至关重要的角色，因为它是稳定血液凝块的纤维网络，也通过与许多血液成分的相互作用而发挥作用。虽然人们对纤维蛋白的力学了解很多，但对纤维蛋白的力学如何影响其生物化学知之甚少。我们发现，机械张力下纤维蛋白的结构变化减少了组织纤溶酶原激活物的结合，组织纤溶酶原激活剂是一种启动裂解的酶。此外，这些结构转变还通过抑制血小板整合素和纤维蛋白之间的结合而导致血小板活化减少。我们的工作表明，纤维蛋白具有内在的机械力-化学反馈环，通过分子结构重排来调节其生物活性。纤维蛋白是构成血液凝块的纤维蛋白网络；由于多尺度的力调节机制，它能够承受非常大的拉伸应变(高达200%)。纤维蛋白也是许多酶和血液因子的生化支架。纤维蛋白的生物力学和生物化学已被独立研究。然而，人们对纤维蛋白生物力学和生物化学是如何耦合的知之甚少：纤维蛋白变形是如何影响其生物化学的？在这项研究中，我们证明了机械诱导的纤维蛋白结构变化会影响纤维蛋白的生物化学。我们发现，纤维蛋白的拉伸变形导致α-螺旋到β-Sheet的分子结构转变，从而减少了组织纤溶酶原激活物(TPA)的结合，组织纤溶酶原激活物是一种启动纤维蛋白溶解的酶。此外，组织型纤溶酶原激活剂与常用的β-Sheet标记硫代黄素T的结合是互斥的，进一步证明了纤维蛋白生化的机械力化学控制。最后，我们证明，由于αIIbβ3整合素结合减少，纤维蛋白的结构变化抑制了血小板对机械应变纤维蛋白的生物活性。我们的工作表明，机械应变在一个优雅的机械力-化学反馈回路中调节纤维蛋白的分子结构和生物活性，这可能延伸到其他纤维生物聚合物。
Fibrin plays a vital role in biology as the fibrous network that stabilizes blood clots and also through interaction with numerous blood components. While much is known about fibrin mechanics, comparatively little is known about how fibrin’s mechanics influence its biochemistry. We show that structural changes in fibrin under mechanical tension reduces binding of tissue plasminogen activator, an enzyme that initiates lysis. Furthermore, these structural transitions also led to decreased platelet activation through suppressed binding between platelet integrins and fibrin. Our work shows that fibrin possesses an intrinsic mechano-chemical feedback loop that regulates its bioactivity via molecular structural rearrangements. 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 α-helices to β-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 β-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 αIIbβ3 integrin binding. Our work shows that mechanical strain regulates fibrin molecular structure and biological activity in an elegant mechano-chemical feedback loop, which possibly extends to other fibrous biopolymers.
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DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Biancalana M;Koide S
通讯作者：
Koide S
DOI：
10.1039/c1ib00085c
发表时间：
2012-01
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
--
作者：
Sun JE;Vranic J;Composto RJ;Streu C;Billings PC;Bennett JS;Weisel JW;Litvinov RI
通讯作者：
Litvinov RI
影响因子：
3.4
作者：
Kurniawan, Nicholas A.;Vos, Bart E.;Koenderink, Gijsje H.
通讯作者：
Koenderink, Gijsje H.
影响因子：
9.7
作者：
Leonidakis, Kimon Alexandros;Bhattacharya, Pinaki;Van Oosterwyck, Hans
通讯作者：
Van Oosterwyck, Hans
影响因子：
2.9
作者：
KLOCZEWIAK, M;TIMMONS, S;HAWIGER, J
通讯作者：
HAWIGER, J