Molecular dynamics simulation of force-regulated interaction between talin and Rap1b_Journal of Biomedical Engineering

Authors：

YU Zhe ¹ , JI Yanru ¹ , HUANG Wenhua ² ,  FANG Ying ¹ ,  WU Jianhua ¹

1. School of Bioscience & Bioengineering, South China University of Technology, Guangzhou 510006, P. R. China;
2. National Key Discipline of Human Anatomy, School of Basic Medical Science, Southern Medical University, Guangdong Provincial Key Laboratory of Medical Biomechanics, Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangzhou 510515, P. R. China;

Corresponding author：

FANG Ying, Email: wujianhua@scut.edu.cn; WU Jianhua, Email: wujianhua@scut.edu.cn

Keywords：

Talin-1; Rap1b; Molecular dynamics simulation; Biphasic force-dependent

DOI：

10.7507/1001-5515.202208022

Video：

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The binding of talin-F0 domain to ras-related protein 1b (Rap1b) plays an important role in the formation of thrombosis. However, since talin is a force-sensitive protein, it remains unclear whether and how force regulates the talin-F0/Rap1b interaction. To explore the effect of force on the binding affinity and the dynamics mechanisms of talin-F0/Rap1b, molecular dynamics simulation was used to observe and compare the changes in functional and conformational information of the complex under different forces. Our results showed that when the complex was subjected to tensile forces, there were at least two dissociation pathways with significantly different mechanical strengths. The key event determining the mechanical strength difference between the two pathways was whether the β4 sheet of the F0 domain was pulled away from the original β1-β4 parallel structure. As the force increased, the talin-F0/Rap1b interaction first strengthened and then weakened, exhibiting the signature of a transition from catch bonds to slip bonds. The mechanical load of 20 pN increased the interaction index of two residue pairs, ASP⁵⁴-ARG⁴¹ and GLN¹⁸-THR⁶⁵, which resulted in a significant increase in the affinity of the complex. This study predicts the regulatory mechanism of the talin-F0/Rap1b interaction by forces in the intracellular environment and provides novel ideas for the treatment of related diseases and drug development.

Citation： YU Zhe, JI Yanru, HUANG Wenhua, FANG Ying, WU Jianhua. Molecular dynamics simulation of force-regulated interaction between talin and Rap1b. Journal of Biomedical Engineering, 2023, 40(4): 645-653. doi: 10.7507/1001-5515.202208022 Copy

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3.	Nieswandt B, Moser M, Pleines I, et al. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J Exp Med, 2007, 204(13): 3113-3118.
4.	Wegener K L, Partridge A W, Han J, et al. Structural basis of integrin activation by talin. Cell, 2007, 128(1): 171-182.
5.	Dedden D, Schumacher S, Kelley C F, et al. The architecture of talin1 reveals an autoinhibition mechanism. Cell, 2019, 179(1): 120-131. e113.
6.	Bromberger T, Zhu L, Klapproth S, et al. Rap1 and membrane lipids cooperatively recruit talin to trigger integrin activation. J Cell Sci, 2019, 132(21): jcs235531.
7.	Bromberger T, Klapproth S, Rohwedder I, et al. Direct Rap1/Talin1 interaction regulates platelet and neutrophil integrin activity in mice. Blood, 2018, 132(26): 2754-2762.
8.	Zhu L, Yang J, Bromberger T, et al. Structure of Rap1b bound to talin reveals a pathway for triggering integrin activation. Nat Commun, 2017, 8(1): 1-12.
9.	Camp D, Haage A, Solianova V, et al. Direct binding of Talin to Rap1 is required for cell-ECM adhesion in Drosophila. J Cell Sci, 2018, 131(24): jcs225144.
10.	Gingras A R, Lagarrigue F, Cuevas M N, et al. Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem. J Cell Biol, 2019, 218(6): 1799-1809.
11.	Austen K, Ringer P, Mehlich A, et al. Extracellular rigidity sensing by talin isoform-specific mechanical linkages. Nat Cell Biol, 2015, 17(12): 1597-1606.
12.	Kumar A, Ouyang M, Van den Dries K, et al. Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. J Cell Biol, 2016, 213(3): 371-383.
13.	Goult B T, Brown N H, Schwartz M A. Talin in mechanotransduction and mechanomemory at a glance. J Cell Sci, 2021, 134(20): jcs258749.
14.	Chakraborty S, Banerjee S, Raina M, et al. Force-directed “Mechanointeractome” of talin–integrin. Biochemistry, 2019, 58(47): 4677-4695.
15.	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: 4605.
16.	Owen L M, Bax N A, Weis W I, et al. The C-terminal actin-binding domain of talin forms an asymmetric catch bond with F-actin. Proc Natl Acad Sci U S A, 2022, 119(10): e2109329119.
17.	Yao M, Goult B T, Chen H, et al. Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation. Sci Rep, 2014, 4: 4610.
18.	Gingras A R, Bate N, Goult B T, et al. The structure of the C-terminal actin-binding domain of talin. EMBO J, 2008, 27(2): 458-469.
19.	Srivastava J, Barreiro G, Groscurth S, et al. Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling. Proc Natl Acad Sci U S A, 2008, 105(38): 14436-14441.
20.	Anthis N J, Wegener K L, Critchley D R, et al. Structural diversity in integrin/talin interactions. Structure, 2010, 18(12): 1654-1666.
21.	Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph, 1996, 14(1): 33-38.
22.	Phillips J C, Braun R, Wang W, et al. Scalable molecular dynamics with NAMD. J Comput Chem, 2005, 26(16): 1781-1802.
23.	Brooks B R, Brooks III C L, Mackerell Jr A D, et al. CHARMM: the biomolecular simulation program. J Comput Chem, 2009, 30(10): 1545-1614.
24.	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.
25.	谢旭斌, 刘文平, 吴建华, 等. 采用分子动力学模拟方法探究Ca²⁺对VWF-A2结构域稳定性的影响. 医用生物力学, 2018, 33(3): 248-254.
26.	李圆圆, 宁志龙, 吴建华, 等. A3/A1复合物对接及结构域之间相互作用的分子动力学研究. 医用生物力学, 2020, 35(2): 195-201, 215.
27.	Liao Z, Gingras A R, Lagarrigue F, et al. Optogenetics-based localization of talin to the plasma membrane promotes activation of β3 integrins. J Biol Chem, 2021, 296: 100675.
28.	Goult B T, Bouaouina M, Elliott P R, et al. Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation. EMBO J, 2010, 29(6): 1069-1080.
29.	Chen W, Lou J, Zhu C. Forcing switch from short-to intermediate-and long-lived states of the αA domain generates LFA-1/ICAM-1 catch bonds. J Biol Chem, 2010, 285(46): 35967-35978.
30.	Zhang Y, Lin Z, Fang Y, et al. Prediction of catch-slip bond transition of kindlin2/β3 integrin via steered molecular dynamics simulation. J Chem Inf Model, 2020, 60(10): 5132-5141.

1. Huang J, Li X, Shi X, et al. Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting. J Hematol Oncol, 2019, 12(1): 1-22.
2. Bachmann M, Kukkurainen S, Hytonen V P, et al. Cell adhesion by integrins. Physiol Rev, 2019, 99(4): 1655-1699.
3. Nieswandt B, Moser M, Pleines I, et al. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J Exp Med, 2007, 204(13): 3113-3118.
4. Wegener K L, Partridge A W, Han J, et al. Structural basis of integrin activation by talin. Cell, 2007, 128(1): 171-182.
5. Dedden D, Schumacher S, Kelley C F, et al. The architecture of talin1 reveals an autoinhibition mechanism. Cell, 2019, 179(1): 120-131. e113.
6. Bromberger T, Zhu L, Klapproth S, et al. Rap1 and membrane lipids cooperatively recruit talin to trigger integrin activation. J Cell Sci, 2019, 132(21): jcs235531.
7. Bromberger T, Klapproth S, Rohwedder I, et al. Direct Rap1/Talin1 interaction regulates platelet and neutrophil integrin activity in mice. Blood, 2018, 132(26): 2754-2762.
8. Zhu L, Yang J, Bromberger T, et al. Structure of Rap1b bound to talin reveals a pathway for triggering integrin activation. Nat Commun, 2017, 8(1): 1-12.
9. Camp D, Haage A, Solianova V, et al. Direct binding of Talin to Rap1 is required for cell-ECM adhesion in Drosophila. J Cell Sci, 2018, 131(24): jcs225144.
10. Gingras A R, Lagarrigue F, Cuevas M N, et al. Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem. J Cell Biol, 2019, 218(6): 1799-1809.
11. Austen K, Ringer P, Mehlich A, et al. Extracellular rigidity sensing by talin isoform-specific mechanical linkages. Nat Cell Biol, 2015, 17(12): 1597-1606.
12. Kumar A, Ouyang M, Van den Dries K, et al. Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. J Cell Biol, 2016, 213(3): 371-383.
13. Goult B T, Brown N H, Schwartz M A. Talin in mechanotransduction and mechanomemory at a glance. J Cell Sci, 2021, 134(20): jcs258749.
14. Chakraborty S, Banerjee S, Raina M, et al. Force-directed “Mechanointeractome” of talin–integrin. Biochemistry, 2019, 58(47): 4677-4695.
15. 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: 4605.
16. Owen L M, Bax N A, Weis W I, et al. The C-terminal actin-binding domain of talin forms an asymmetric catch bond with F-actin. Proc Natl Acad Sci U S A, 2022, 119(10): e2109329119.
17. Yao M, Goult B T, Chen H, et al. Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation. Sci Rep, 2014, 4: 4610.
18. Gingras A R, Bate N, Goult B T, et al. The structure of the C-terminal actin-binding domain of talin. EMBO J, 2008, 27(2): 458-469.
19. Srivastava J, Barreiro G, Groscurth S, et al. Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling. Proc Natl Acad Sci U S A, 2008, 105(38): 14436-14441.
20. Anthis N J, Wegener K L, Critchley D R, et al. Structural diversity in integrin/talin interactions. Structure, 2010, 18(12): 1654-1666.
21. Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph, 1996, 14(1): 33-38.
22. Phillips J C, Braun R, Wang W, et al. Scalable molecular dynamics with NAMD. J Comput Chem, 2005, 26(16): 1781-1802.
23. Brooks B R, Brooks III C L, Mackerell Jr A D, et al. CHARMM: the biomolecular simulation program. J Comput Chem, 2009, 30(10): 1545-1614.
24. 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.
25. 谢旭斌, 刘文平, 吴建华, 等. 采用分子动力学模拟方法探究Ca²⁺对VWF-A2结构域稳定性的影响. 医用生物力学, 2018, 33(3): 248-254.
26. 李圆圆, 宁志龙, 吴建华, 等. A3/A1复合物对接及结构域之间相互作用的分子动力学研究. 医用生物力学, 2020, 35(2): 195-201, 215.
27. Liao Z, Gingras A R, Lagarrigue F, et al. Optogenetics-based localization of talin to the plasma membrane promotes activation of β3 integrins. J Biol Chem, 2021, 296: 100675.
28. Goult B T, Bouaouina M, Elliott P R, et al. Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation. EMBO J, 2010, 29(6): 1069-1080.
29. Chen W, Lou J, Zhu C. Forcing switch from short-to intermediate-and long-lived states of the αA domain generates LFA-1/ICAM-1 catch bonds. J Biol Chem, 2010, 285(46): 35967-35978.
30. Zhang Y, Lin Z, Fang Y, et al. Prediction of catch-slip bond transition of kindlin2/β3 integrin via steered molecular dynamics simulation. J Chem Inf Model, 2020, 60(10): 5132-5141.

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