Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain of Platelet Integrin αIIbβ3 (Platelet Membrane Glycoprotein: GPIIb–IIIa)

Masamitsu Nakayama; Shinichi Goto; Shinya Goto

doi:10.1055/a-2247-9438

TH Open, Table of Contents

CC BY 4.0 · TH Open 2024; 08(01): e96-e105
DOI: 10.1055/a-2247-9438

Original Article

Development of the Integrated Computer Simulation Model of the Intracellular, Transmembrane, and Extracellular Domain of Platelet Integrin α_IIbβ₃ (Platelet Membrane Glycoprotein: GPIIb–IIIa)

Authors

Masamitsu Nakayama

¹Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan
Shinichi Goto ^*

¹Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan
Shinya Goto

¹Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan

Abstract

Background The structure and functions of the extracellular domain of platelet integrin α_IIbβ₃ (platelet membrane glycoprotein: GPIIb–IIIa) change substantially upon platelet activation. However, the stability of the integrated model of extracellular/transmembrane/intracellular domains of integrin α_IIbβ₃ with the inactive state of the extracellular domain has not been clarified.

Methods The integrated model of integrin α_IIbβ₃ was developed by combining the extracellular domain adopted from the crystal structure and the transmembrane and intracellular domain obtained by Nuclear Magnetic Resonace (NMR). The transmembrane domain was settled into the phosphatidylcholine (2-oleoyl-1-palmitoyl-sn-glycerol-3-phosphocholine (POPC)) lipid bilayer model. The position coordinates and velocity vectors of all atoms and water molecules around them were calculated by molecular dynamic (MD) simulation with the use of Chemistry at Harvard Macromolecular Mechanics force field in every 2 × 10⁻¹⁵ seconds.

Results The root-mean-square deviations (RMSDs) of atoms constructing the integrated α_IIbβ₃ model apparently stabilized at approximately 23 Å after 200 ns of calculation. However, minor fluctuation persisted during the entire calculation period of 650 ns. The RMSDs of both α_IIb and β₃ showed similar trends before 200 ns. The RMSD of β₃ apparently stabilized approximately at 15 Å at 400 ns with persisting minor fluctuation afterward, while the structural fluctuation in α_IIb persisted throughout the 650 ns calculation period.

Conclusion In conclusion, the integrated model of the intracellular, transmembrane, and extracellular domain of integrin α_IIbβ₃ suggested persisting fluctuation even after convergence of MD calculation.

Keywords

platelet - integrin α_IIbβ₃ - molecular dynamic simulation - GPIIb/IIIa

Full Text

References

References
1 Coller BS, Shattil SJ. The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood 2008; 112 (08) 3011-3025
2 Nurden AT, Pillois X, Wilcox DA. Glanzmann thrombasthenia: state of the art and future directions. In: Seminars in thrombosis and hemostasis. Thieme Medical Publishers; 2013: 642-655
3 Curtis BR. Recent progress in understanding the pathogenesis of fetal and neonatal alloimmune thrombocytopenia. Br J Haematol 2015; 171 (05) 671-682
4 Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999; 353 (9148) 227-231
5 Tozer EC, Liddington RC, Sutcliffe MJ, Smeeton AH, Loftus JC. Ligand binding to integrin alphaIIbbeta3 is dependent on a MIDAS-like domain in the beta3 subunit. J Biol Chem 1996; 271 (36) 21978-21984
6 Bajt ML, Loftus JC. Mutation of a ligand binding domain of beta 3 integrin. Integral role of oxygenated residues in alpha IIb beta 3 (GPIIb-IIIa) receptor function. J Biol Chem 1994; 269 (33) 20913-20919
7 Xiao T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature 2004; 432 (7013) 59-67
8 Wegener KL, Partridge AW, Han J. et al. Structural basis of integrin activation by talin. Cell 2007; 128 (01) 171-182
9 Chrzanowska-Wodnicka M, Smyth SS, Schoenwaelder SM, Fischer TH, White II GC. Rap1b is required for normal platelet function and hemostasis in mice. J Clin Invest 2005; 115 (03) 680-687
10 Moser M, Nieswandt B, Ussar S, Pozgajova M, Fässler R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 2008; 14 (03) 325-330
11 Ma YQ, Qin J, Wu C, Plow EF. Kindlin-2 (Mig-2): a co-activator of beta3 integrins. J Cell Biol 2008; 181 (03) 439-446
12 Tong D, Soley N, Kolasangiani R, Schwartz MA, Bidone TC. Integrin α_IIbβ₃ intermediates: from molecular dynamics to adhesion assembly. Biophys J 2023; 122 (03) 533-543
13 Karplus M, McCammon JA. Molecular dynamics simulations of biomolecules. Nat Struct Biol 2002; 9 (09) 646-652
14 Karplus M, Petsko GA. Molecular dynamics simulations in biology. Nature 1990; 347 (6294) 631-639
15 Karplus M, Kuriyan J. Molecular dynamics and protein function. Proc Natl Acad Sci U S A 2005; 102 (19) 6679-6685
16 Kozono D, Yasui M, King LS, Agre P. Aquaporin water channels: atomic structure molecular dynamics meet clinical medicine. J Clin Invest 2002; 109 (11) 1395-1399
17 Hub JS, Grubmüller H, de Groot BL. Dynamics and energetics of permeation through aquaporins. What do we learn from molecular dynamics simulations?. Handb Exp Pharmacol 2009; (190) 57-76
18 Savage B, Saldívar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84 (02) 289-297
19 Goto S, Ikeda Y, Saldívar E, Ruggeri ZM. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J Clin Invest 1998; 101 (02) 479-486
20 Shiozaki S, Takagi S, Goto S. Prediction of molecular interaction between platelet glycoprotein Ibα and von Willebrand factor using molecular dynamics simulations. J Atheroscler Thromb 2016; 23 (04) 455-464
21 Goto S, Oka H, Ayabe K. et al. Prediction of binding characteristics between von Willebrand factor and platelet glycoprotein Ibα with various mutations by molecular dynamic simulation. Thromb Res 2019; 184: 129-135
22 Haas TA, Plow EF. Development of a structural model for the cytoplasmic domain of an integrin. Protein Eng 1997; 10 (12) 1395-1405
23 Goguet M, Narwani TJ, Petermann R, Jallu V, de Brevern AG. In silico analysis of Glanzmann variants of Calf-1 domain of α_IIbβ₃ integrin revealed dynamic allosteric effect. Sci Rep 2017; 7 (01) 8001
24 Jallu V, Poulain P, Fuchs PF, Kaplan C, de Brevern AG. Modeling and molecular dynamics simulations of the V33 variant of the integrin subunit β3: Structural comparison with the L33 (HPA-1a) and P33 (HPA-1b) variants. Biochimie 2014; 105: 84-90
25 Zhu J, Luo BH, Xiao T, Zhang C, Nishida N, Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell 2008; 32 (06) 849-861
26 Lentz BR. Exposure of platelet membrane phosphatidylserine regulates blood coagulation. Prog Lipid Res 2003; 42 (05) 423-438
27 Janosi L, Gorfe AA. Simulating POPC and POPC/POPG bilayers: conserved packing and altered surface reactivity. J Chem Theory Comput 2010; 6 (10) 3267-3273
28 Roka-Moiia Y, Walk R, Palomares DE. et al. Platelet activation via shear stress exposure induces a differing pattern of biomarkers of activation versus biochemical agonists. Thromb Haemost 2020; 120 (05) 776-792
29 Yang J, Ma Y-Q, Page RC, Misra S, Plow EF, Qin J. Structure of an integrin alphaIIb beta3 transmembrane-cytoplasmic heterocomplex provides insight into integrin activation. Proc Natl Acad Sci U S A 2009; 106 (42) 17729-17734
30 Adair BD, Yeager M. Three-dimensional model of the human platelet integrin alpha IIbbeta 3 based on electron cryomicroscopy and x-ray crystallography. Proc Natl Acad Sci U S A 2002; 99 (22) 14059-14064
31 Boonstra S, Onck PR, Giessen Ev. CHARMM TIP3P water model suppresses peptide folding by solvating the unfolded state. J Phys Chem B 2016; 120 (15) 3692-3698
32 Wang L, O'Mara ML. Effect of the force field on molecular dynamics simulations of the multidrug efflux protein P-glycoprotein. J Chem Theory Comput 2021; 17 (10) 6491-6508
33 Janowski PA, Liu C, Deckman J, Case DA. Molecular dynamics simulation of triclinic lysozyme in a crystal lattice. Protein Sci 2016; 25 (01) 87-102
34 Takagi J, Petre BM, Walz T, Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 2002; 110 (05) 599-511
35 D'Souza SE, Ginsberg MH, Burke TA, Plow EF. The ligand binding site of the platelet integrin receptor GPIIb-IIIa is proximal to the second calcium binding domain of its alpha subunit. J Biol Chem 1990; 265 (06) 3440-3446
36 Zhu J, Choi W-S, McCoy JG. et al. Structure-guided design of a high-affinity platelet integrin αIIbβ3 receptor antagonist that disrupts Mg²⁺ binding to the MIDAS. Sci Transl Med 2012; 4 (125) 125ra32
37 Goto S, Tamura N, Ishida H, Ruggeri ZM. Dependence of platelet thrombus stability on sustained glycoprotein IIb/IIIa activation through adenosine 5′-diphosphate receptor stimulation and cyclic calcium signaling. J Am Coll Cardiol 2006; 47 (01) 155-162
38 Rahman A, Stillinger FH. Molecular dynamics study of liquid water. J Chem Phys 1971; 55: 3336-3359
39 Klepeis JL, Lindorff-Larsen K, Dror RO, Shaw DE. Long-timescale molecular dynamics simulations of protein structure and function. Curr Opin Struct Biol 2009; 19 (02) 120-127
40 Marrink S-J, Berendsen HJ. Simulation of water transport through a lipid membrane. J Phys Chem 1994; 98: 4155-4168
41 Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci 2003; 4 (12) 991-1001
42 Interlandi G, Thomas W. The catch bond mechanism between von Willebrand factor and platelet surface receptors investigated by molecular dynamics simulations. Proteins 2010; 78 (11) 2506-2522
43 Tamura N, Goto S, Yokota H, Goto S. Contributing role of mitochondrial energy metabolism on platelet adhesion, activation and thrombus formation under blood flow conditions. Platelets 2022; 33 (07) 1083-1089
44 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
45 Petrich BG, Marchese P, Ruggeri ZM. et al. Talin is required for integrin-mediated platelet function in hemostasis and thrombosis. J Exp Med 2007; 204 (13) 3103-3111
46 Moriarty R, McManus CA, Lambert M. et al. A novel role for the fibrinogen Asn-Gly-Arg (NGR) motif in platelet function. Thromb Haemost 2015; 113 (02) 290-304
47 Xiong JP, Stehle T, Diefenbach B. et al. Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science 2001; 294 (5541) 339-345
48 Lau TL, Dua V, Ulmer TS. Structure of the integrin alphaIIb transmembrane segment. J Biol Chem 2008; 283 (23) 16162-16168
49 O'Toole TE, Mandelman D, Forsyth J, Shattil SJ, Plow EF, Ginsberg MH. Modulation of the affinity of integrin α IIb β 3 (GPIIb-IIIa) by the cytoplasmic domain of α IIb. Science 1991; 254 (5033) 845-847
50 Zhu J, Luo B-H, Barth P, Schonbrun J, Baker D, Springer TA. The structure of a receptor with two associating transmembrane domains on the cell surface: integrin alphaIIbbeta3. Mol Cell 2009; 34 (02) 234-249
51 van Kruchten R, Mattheij NJ, Saunders C. et al. Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation. Blood 2013; 121 (10) 1850-1857
52 Ulmer TS, Calderwood DA, Ginsberg MH, Campbell ID. Domain-specific interactions of talin with the membrane-proximal region of the integrin beta3 subunit. Biochemistry 2003; 42 (27) 8307-8312
53 Haas TA, Plow EF. The cytoplasmic domain of alphaIIb beta3. A ternary complex of the integrin alpha and beta subunits and a divalent cation. J Biol Chem 1996; 271 (11) 6017-6026
54 Kufareva I, Abagyan R. Methods of protein structure comparison. In: Homology modeling. Springer; 2011: 231-257