Molecular dynamics simulation of force-regulated interaction between glycoprotein Ib<b>α</b> and filamin_Journal of Biomedical Engineering

Authors：

TAO Rencai , XIE Xubin , WU Jianhua ,  FANG Ying

School of Bioscience & Bioengineering, South China University of Technology, Guangzhou 510006, P. R. China;

Corresponding author：

FANG Ying, Email: yfang@scut.edu.cn

Keywords：

Filamin a; Glycoprotein Ibα; Platelet; Molecular dynamic simulation; Force signal

DOI：

10.7507/1001-5515.202302043

Video：

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In resting platelets, the 17^th domain of filamin a (FLNa17) constitutively binds to the platelet membrane glycoprotein Ibα (GPIbα) at its cytoplasmic tail (GPIbα-CT) and inhibits the downstream signal activation, while the binding of ligand and blood shear force can activate platelets. To imitate the pull force transmitted from the extracellular ligand of GPIbα and the lateral tension from platelet cytoskeleton deformation, two pulling modes were applied on the GPIbα-CT/FLNa17 complex, and the molecular dynamics simulation method was used to explore the mechanical regulation on the affinity and mechanical stability of the complex. In this study, at first, nine pairs of key hydrogen bonds on the interface between GPIbα-CT and FLNa17 were identified, which was the basis for maintaining the complex structural stability. Secondly, it was found that these hydrogen bonding networks would be broken down and lead to the dissociation of FLNa17 from GPIbα-CT only under the axial pull force; but, under the lateral tension, the secondary structures at both terminals of FLNa17 would unfold to protect the interface of the GPIbα-CT/FLNa17 complex from mechanical damage. In the range of 0~40 pN, the increase of pull force promoted outward-rotation of the nitrogen atom of the 563^rd phenylalanine (PHE⁵⁶³-N) at GPIbα-CT and the dissociation of the complex. This study for the first time revealed that the extracellular ligand-transmitted axial force could more effectively relieve the inhibition of FLNa17 on the downstream signal of GPIbα than pure mechanical tension at the atomic level, and would be useful for further understanding the platelet intracellular force-regulated signal pathway.

Citation： TAO Rencai, XIE Xubin, WU Jianhua, FANG Ying. Molecular dynamics simulation of force-regulated interaction between glycoprotein Ibα and filamin. Journal of Biomedical Engineering, 2023, 40(5): 876-885. doi: 10.7507/1001-5515.202302043 Copy

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2.	Mo X, Liu L, López J A, et al. Transmembrane domains are critical to the interaction between platelet glycoprotein V and glycoprotein Ib-IX complex. J Thromb Haemost, 2012, 10(9): 1875-1886.
3.	Canobbio I, Balduini C, Torti M. Signalling through the platelet glycoprotein Ib-V-IX complex. Cell Signal, 2004, 16(12): 1329-1344.
4.	Du X, Fox J E, Pei S. Identification of a binding sequence for the 14-3-3 protein within the cytoplasmic domain of the adhesion receptor, platelet glycoprotein Ib alpha. J Biol Chem, 1996, 271(13): 7362-7367.
5.	Okita J R, Pidard D, Newman P J, et al. On the association of glycoprotein Ib and actin-binding protein in human platelets. J Cell Biol, 1985, 100(1): 317-321.
6.	Arce N A, Cao W, Brown A K, et al. Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module. Nat Commun, 2021, 12(1): 2360.
7.	Fu H, Jiang Y, Yang D, et al. Flow-induced elongation of von Willebrand factor precedes tension-dependent activation. Nat Commun, 2017, 8(1): 324.
8.	Springer T A. von Willebrand factor, Jedi knight of the bloodstream. Blood, 2014, 124(9): 1412-1425.
9.	Estevez B, Kim K, Delaney MK, et al. Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation. Blood, 2016, 127(5): 626-636.
10.	Shen C, Liu M, Xu R, et al. The 14-3-3ζ-c-Src-integrin-β3 complex is vital for platelet activation. Blood, 2020, 136(8): 974-988.
11.	Chen Y, Ju LA, Zhou F, et al. An integrin αIIbβ3 intermediate affinity state mediates biomechanical platelet aggregation. Nat Mater, 2019, 18(7): 760-769.
12.	Nakamura F, Osborn T M, Hartemink C A, et al. Structural basis of filamin A functions. J Cell Biol, 2007, 179(5): 1011-1025.
13.	Pudas R, Kiema T R, Butler P J, et al. Structural basis for vertebrate filamin dimerization. Structure, 2005, 13(1): 111-119.
14.	Seo M D, Seok S H, Im H, et al. Crystal structure of the dimerization domain of human filamin A. Proteins, 2009, 75(1): 258-263.
15.	Zhou A X, Hartwig J H, Akyürek L M. Filamins in cell signaling, transcription and organ development. Trends Cell Biol, 2010, 20(2): 113-123.
16.	Feng S, Reséndiz J C, Lu X, et al. Filamin A binding to the cytoplasmic tail of glycoprotein Ibalpha regulates von Willebrand factor-induced platelet activation. Blood, 2003, 102(6): 2122-2129.
17.	Williamson D, Pikovski I, Cranmer S L, et al. Interaction between platelet glycoprotein Ibalpha and filamin-1 is essential for glycoprotein Ib/IX receptor anchorage at high shear. J Biol Chem, 2002, 277(3): 2151-2159.
18.	Nakamura F, Stossel T P, Hartwig J H. The filamins: organizers of cell structure and function. Cell Adh Migr, 2011, 5(2): 160-169.
19.	Kiema T, Lad Y, Jiang P, et al. The molecular basis of filamin binding to integrins and competition with talin. Mol Cell, 2006, 21(3): 337-347.
20.	Nakamura F, Pudas R, Heikkinen O, et al. The structure of the GPIb-filamin A complex. Blood, 2006, 107(5): 1925-1932.
21.	Qiu Y, Ciciliano J, Myers D R, et al. Platelets and physics: How platelets "feel" and respond to their mechanical microenvironment. Blood Rev, 2015, 29(6): 377-386.
22.	Ju L, Chen Y, Zhou F, et al. Von Willebrand factor-A1 domain binds platelet glycoprotein Ibα in multiple states with distinctive force-dependent dissociation kinetics. Thromb Res, 2015, 136(3): 606-612.
23.	Chen Z, Mondal N K, Ding J, et al. Activation and shedding of platelet glycoprotein IIb/IIIa under non-physiological shear stress. Mol Cell Biochem, 2015, 409(1-2): 93-101.
24.	Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph, 1996, 14(1): 33-38.
25.	李雨峰, 方颖, 吴建华. 利用分子动力学模拟探究力学信号对CD44/FERM复合物结构的影响. 生物医学工程学杂志, 2018, 35(4): 501-508.
26.	Su S, Ling Y, Fang Y, et al. Force-enhanced biophysical connectivity of platelet β3 integrin signaling through Talin is predicted by steered molecular dynamics simulations. Sci Rep, 2022, 12(1): 4605.
27.	Ji Y, Fang Y, Wu J. Tension enhances the binding affinity of β1 integrin by clamping Talin tightly: an insight from steered molecular dynamics simulations. J Chem Inf Model, 2022, 62(22): 5688-5698.
28.	Liu G, Fang Y, Wu J. A mechanism for localized dynamics-driven affinity regulation of the binding of von Willebrand factor to platelet glycoprotein Ibα. J Biol Chem, 2013, 288(37): 26658-26667.
29.	Rosa J P, Raslova H, Bryckaert M. Filamin A: key actor in platelet biology. Blood, 2019, 134(16): 1279-1288.
30.	Ringer P, Colo G, Fässler R, et al. Sensing the mechano-chemical properties of the extracellular matrix. Matrix Biol, 2017, 64: 6-16.
31.	Oria R, Wiegand T, Escribano J, et al. Force loading explains spatial sensing of ligands by cells. Nature, 2017, 552(7684): 219-224.
32.	Ju L, Chen Y, Xue L, et al. Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals. Elife, 2016, 5: e15447.
33.	Merten M, Chow T, Hellums J D, et al. A new role for P-selectin in shear-induced platelet aggregation. Circulation, 2000, 102(17): 2045-2050.

1. Luo S Z, Mo X, Afshar-Kharghan V, et al. Glycoprotein Ibalpha forms disulfide bonds with 2 glycoprotein Ibbeta subunits in the resting platelet. Blood, 2007, 109(2): 603-609.
2. Mo X, Liu L, López J A, et al. Transmembrane domains are critical to the interaction between platelet glycoprotein V and glycoprotein Ib-IX complex. J Thromb Haemost, 2012, 10(9): 1875-1886.
3. Canobbio I, Balduini C, Torti M. Signalling through the platelet glycoprotein Ib-V-IX complex. Cell Signal, 2004, 16(12): 1329-1344.
4. Du X, Fox J E, Pei S. Identification of a binding sequence for the 14-3-3 protein within the cytoplasmic domain of the adhesion receptor, platelet glycoprotein Ib alpha. J Biol Chem, 1996, 271(13): 7362-7367.
5. Okita J R, Pidard D, Newman P J, et al. On the association of glycoprotein Ib and actin-binding protein in human platelets. J Cell Biol, 1985, 100(1): 317-321.
6. Arce N A, Cao W, Brown A K, et al. Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module. Nat Commun, 2021, 12(1): 2360.
7. Fu H, Jiang Y, Yang D, et al. Flow-induced elongation of von Willebrand factor precedes tension-dependent activation. Nat Commun, 2017, 8(1): 324.
8. Springer T A. von Willebrand factor, Jedi knight of the bloodstream. Blood, 2014, 124(9): 1412-1425.
9. Estevez B, Kim K, Delaney MK, et al. Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation. Blood, 2016, 127(5): 626-636.
10. Shen C, Liu M, Xu R, et al. The 14-3-3ζ-c-Src-integrin-β3 complex is vital for platelet activation. Blood, 2020, 136(8): 974-988.
11. Chen Y, Ju LA, Zhou F, et al. An integrin αIIbβ3 intermediate affinity state mediates biomechanical platelet aggregation. Nat Mater, 2019, 18(7): 760-769.
12. Nakamura F, Osborn T M, Hartemink C A, et al. Structural basis of filamin A functions. J Cell Biol, 2007, 179(5): 1011-1025.
13. Pudas R, Kiema T R, Butler P J, et al. Structural basis for vertebrate filamin dimerization. Structure, 2005, 13(1): 111-119.
14. Seo M D, Seok S H, Im H, et al. Crystal structure of the dimerization domain of human filamin A. Proteins, 2009, 75(1): 258-263.
15. Zhou A X, Hartwig J H, Akyürek L M. Filamins in cell signaling, transcription and organ development. Trends Cell Biol, 2010, 20(2): 113-123.
16. Feng S, Reséndiz J C, Lu X, et al. Filamin A binding to the cytoplasmic tail of glycoprotein Ibalpha regulates von Willebrand factor-induced platelet activation. Blood, 2003, 102(6): 2122-2129.
17. Williamson D, Pikovski I, Cranmer S L, et al. Interaction between platelet glycoprotein Ibalpha and filamin-1 is essential for glycoprotein Ib/IX receptor anchorage at high shear. J Biol Chem, 2002, 277(3): 2151-2159.
18. Nakamura F, Stossel T P, Hartwig J H. The filamins: organizers of cell structure and function. Cell Adh Migr, 2011, 5(2): 160-169.
19. Kiema T, Lad Y, Jiang P, et al. The molecular basis of filamin binding to integrins and competition with talin. Mol Cell, 2006, 21(3): 337-347.
20. Nakamura F, Pudas R, Heikkinen O, et al. The structure of the GPIb-filamin A complex. Blood, 2006, 107(5): 1925-1932.
21. Qiu Y, Ciciliano J, Myers D R, et al. Platelets and physics: How platelets "feel" and respond to their mechanical microenvironment. Blood Rev, 2015, 29(6): 377-386.
22. Ju L, Chen Y, Zhou F, et al. Von Willebrand factor-A1 domain binds platelet glycoprotein Ibα in multiple states with distinctive force-dependent dissociation kinetics. Thromb Res, 2015, 136(3): 606-612.
23. Chen Z, Mondal N K, Ding J, et al. Activation and shedding of platelet glycoprotein IIb/IIIa under non-physiological shear stress. Mol Cell Biochem, 2015, 409(1-2): 93-101.
24. Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph, 1996, 14(1): 33-38.
25. 李雨峰, 方颖, 吴建华. 利用分子动力学模拟探究力学信号对CD44/FERM复合物结构的影响. 生物医学工程学杂志, 2018, 35(4): 501-508.
26. Su S, Ling Y, Fang Y, et al. Force-enhanced biophysical connectivity of platelet β3 integrin signaling through Talin is predicted by steered molecular dynamics simulations. Sci Rep, 2022, 12(1): 4605.
27. Ji Y, Fang Y, Wu J. Tension enhances the binding affinity of β1 integrin by clamping Talin tightly: an insight from steered molecular dynamics simulations. J Chem Inf Model, 2022, 62(22): 5688-5698.
28. Liu G, Fang Y, Wu J. A mechanism for localized dynamics-driven affinity regulation of the binding of von Willebrand factor to platelet glycoprotein Ibα. J Biol Chem, 2013, 288(37): 26658-26667.
29. Rosa J P, Raslova H, Bryckaert M. Filamin A: key actor in platelet biology. Blood, 2019, 134(16): 1279-1288.
30. Ringer P, Colo G, Fässler R, et al. Sensing the mechano-chemical properties of the extracellular matrix. Matrix Biol, 2017, 64: 6-16.
31. Oria R, Wiegand T, Escribano J, et al. Force loading explains spatial sensing of ligands by cells. Nature, 2017, 552(7684): 219-224.
32. Ju L, Chen Y, Xue L, et al. Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals. Elife, 2016, 5: e15447.
33. Merten M, Chow T, Hellums J D, et al. A new role for P-selectin in shear-induced platelet aggregation. Circulation, 2000, 102(17): 2045-2050.

Journal of Biomedical Engineering

Molecular dynamics simulation of force-regulated interaction between glycoprotein Ibα and filamin

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