Molecular architecture and platelet-activating properties of small immune complexes assembled on heparin and platelet factor 4.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
11 Mar 2024
11 Mar 2024
Historique:
received:
21
02
2023
accepted:
27
02
2024
medline:
12
3
2024
pubmed:
12
3
2024
entrez:
12
3
2024
Statut:
epublish
Résumé
Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin leading to a reduction in circulating platelets with an increased risk of thrombosis. It is precipitated by polymerized immune complexes consisting of pathogenic antibodies that recognize a small chemokine platelet factor 4 (PF4) bound to heparin. Characterization of these immune complexes is extremely challenging due to the enormous structural heterogeneity of such macromolecular assemblies and their constituents. Native mass spectrometry demonstrates that up to three PF4 tetramers can be assembled on a heparin chain, consistent with the molecular modeling studies showing facile polyanion wrapping along the polycationic belt on the PF4 surface. Although these assemblies can accommodate a maximum of only two antibodies, the resulting immune complexes are capable of platelet activation despite their modest size. Taken together, these studies provide further insight into molecular mechanisms of HIT and other immune disorders where anti-PF4 antibodies play a central role.
Identifiants
pubmed: 38467823
doi: 10.1038/s42003-024-05982-4
pii: 10.1038/s42003-024-05982-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
308Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM112666
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Karshovska, E., Weber, C. & von Hundelshausen, P. Platelet chemokines in health and disease. Thromb. Haemost. 110, 894–902 (2013).
pubmed: 23783401
doi: 10.1160/TH13-04-0341
Kasper, B. & Petersen, F. Molecular pathways of platelet factor 4/CXCL4 signaling. Eur. J. Cell Biol. 90, 521–526 (2011).
pubmed: 21295372
doi: 10.1016/j.ejcb.2010.12.002
Weismann, R. E. & Tobin, R. W. Arterial embolism occurring during systemic heparin therapy. AMA Arch. Surg. 76, 219–225 (1958).
pubmed: 13497418
doi: 10.1001/archsurg.1958.01280200041005
Ivanov, D. G. et al. Reverse engineering of a pathogenic antibody reveals the molecular mechanism of vaccine-induced immune thrombotic thrombocytopenia. J. Am. Chem. Soc. 145, 25203–25213 (2023).
pubmed: 37949820
doi: 10.1021/jacs.3c07846
Qiao, J. L., Al-Tamimi, M., Baker, R. I., Andrews, R. K. & Gardiner, E. E. The platelet Fc receptor, Fc gamma RIIa. Immunol. Rev. 268, 241–252 (2015).
pubmed: 26497525
doi: 10.1111/imr.12370
Jevtic, S. D. & Nazy, I. The COVID complex: a review of platelet activation and immune complexes in COVID-19. Front. Immunol. 13, 807934 (2022).
pubmed: 35371058
pmcid: 8965558
doi: 10.3389/fimmu.2022.807934
Suvarna, S. et al. Determinants of PF4/heparin immunogenicity. Blood 110, 4253–4260 (2007).
pubmed: 17848616
pmcid: 2234783
doi: 10.1182/blood-2007-08-105098
Rauova, L. et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 105, 131–138 (2005).
pubmed: 15304392
doi: 10.1182/blood-2004-04-1544
Casu, B. & Lindahl, U. Structure and biological interactions of heparin and heparan sulfate. Adv. Carbohydr. Chem. Biochem. 57, 159–206 (2001).
pubmed: 11836942
doi: 10.1016/S0065-2318(01)57017-1
Rabenstein, D. L. Heparin and heparan sulfate: structure and function. Nat. Prod. Rep. 19, 312–331 (2002).
pubmed: 12137280
doi: 10.1039/b100916h
Kim, J. Y. et al. Quantitative pattern analysis of the N-terminally processed isoforms of platelet factor-4 in serum. Rapid Commun. Mass Spectrom. 27, 521–530 (2013).
pubmed: 23322658
doi: 10.1002/rcm.6480
Delcea, M. & Greinacher, A. Biophysical tools to assess the interaction of PF4 with polyanions. Thromb. Haemost. 116, 783–791 (2016).
pubmed: 27658429
doi: 10.1160/TH16-04-0258
Greinacher, A. et al. Close approximation of two platelet factor 4 tetramers by charge neutralization forms the antigens recognized by HIT antibodies. Arterioscler. Thromb. Vasc. Biol. 26, 2386–2393 (2006).
pubmed: 16873726
doi: 10.1161/01.ATV.0000238350.89477.88
Cai, Z. et al. Atomic description of the immune complex involved in heparin-induced thrombocytopenia. Nat. Commun. 6, 8277 (2015).
pubmed: 26391892
doi: 10.1038/ncomms9277
Arepally, G. M. et al. Characterization of a murine monoclonal antibody that mimics heparin-induced thrombocytopenia antibodies. Blood 95, 1533–1540 (2000).
pubmed: 10688805
doi: 10.1182/blood.V95.5.1533.005k01_1533_1540
Stuckey, J. A., St Charles, R. & Edwards, B. F. A model of the platelet factor 4 complex with heparin. Proteins 14, 277–287 (1992).
pubmed: 1409574
doi: 10.1002/prot.340140213
Abzalimov, R. R., Dubin, P. L. & Kaltashov, I. A. Glycosaminoglycans as naturally occurring combinatorial libraries: developing a mass spectrometry-based strategy for characterization of anti-thrombin interaction with low molecular weight heparin and heparin oligomers. Anal. Chem. 79, 6055–6063 (2007).
pubmed: 17658885
doi: 10.1021/ac0710432
Nugent, M. A., Zaia, J. & Spencer, J. L. Heparan sulfate-protein binding specificity. Biochem. (Mosc.) 78, 726–735 (2013).
doi: 10.1134/S0006297913070055
Crown, S. E., Yu, Y., Sweeney, M. D., Leary, J. A. & Handel, T. M. Heterodimerization of CCR2 chemokines and regulation by glycosaminoglycan binding. J. Biol. Chem. 281, 25438–25446 (2006).
pubmed: 16803905
doi: 10.1074/jbc.M601518200
Foreman, D. J. & McLuckey, S. A. Recent developments in gas-phase ion/ion reactions for analytical mass spectrometry. Anal. Chem. 92, 252–266 (2020).
pubmed: 31693342
doi: 10.1021/acs.analchem.9b05014
Abzalimov, R. R. & Kaltashov, I. A. Electrospray ionization mass spectrometry of highly heterogeneous protein systems: protein ion charge state assignment via incomplete charge reduction. Anal. Chem. 82, 7523–7526 (2010).
pubmed: 20731408
doi: 10.1021/ac101848z
Kaltashov, I. A., Ivanov, D. G. & Yang, Y. Mass spectrometry-based methods to characterize highly heterogeneous biopharmaceuticals, vaccines, and nonbiological complex drugs at the intact-mass level. Mass Spectrom. Rev. 43, 139–165 (2024).
pubmed: 36582075
doi: 10.1002/mas.21829
Niu, C., Yang, Y., Huynh, A., Nazy, I. & Kaltashov, I. A. Platelet factor 4 interactions with short heparin oligomers: implications for folding and assembly. Biophys. J. 119, 1371–1379 (2020).
pubmed: 32348723
pmcid: 7567982
doi: 10.1016/j.bpj.2020.04.012
Bisio, A. et al. Determination of the molecular weight of low-molecular-weight heparins by using high-pressure size exclusion chromatography on line with a triple detector array and conventional methods. Molecules 20, 5085–5098 (2015).
pubmed: 25808152
pmcid: 6272732
doi: 10.3390/molecules20035085
Minsky, B. B., Dubin, P. L. & Kaltashov, I. A. Electrostatic forces as dominant interactions between proteins and polyanions: an ESI MS study of fibroblast growth factor binding to heparin oligomers. J. Am. Soc. Mass Spectrom. 28, 758–767 (2017).
pubmed: 28211013
pmcid: 5808462
doi: 10.1007/s13361-017-1596-0
Shi, D. et al. New insights into the binding of PF4 to long heparin oligosaccharides in ultralarge complexes using mass spectrometry. J. Thromb. Haemost. 21, 3608–3618 (2023).
pubmed: 37648114
doi: 10.1016/j.jtha.2023.08.020
Pavlov, G., Finet, S., Tatarenko, K., Korneeva, E. & Ebel, C. Conformation of heparin studied with macromolecular hydrodynamic methods and X-ray scattering. Eur. Biophys. J. 32, 437–449 (2003).
pubmed: 12844240
doi: 10.1007/s00249-003-0316-9
Niu, C., Zhao, Y., Bobst, C. E., Savinov, S. N. & Kaltashov, I. A. Identification of Protein Recognition Elements within Heparin Chains Using Enzymatic Foot-Printing in Solution and Online SEC/MS. Anal. Chem. 92, 7565–7573 (2020).
pubmed: 32347711
pmcid: 8095033
doi: 10.1021/acs.analchem.0c00115
Capila, I. & Linhardt, R. J. Heparin-protein interactions. Angew. Chem. Int. Ed. Engl. 41, 391–412 (2002).
pubmed: 12491369
doi: 10.1002/1521-3773(20020201)41:3<390::AID-ANIE390>3.0.CO;2-B
Gong, F. et al. Processing of macromolecular heparin by heparanase. J. Biol. Chem. 278, 35152–35158 (2003).
pubmed: 12837765
doi: 10.1074/jbc.M300925200
Kjellen, L. & Lindahl, U. Specificity of glycosaminoglycan-protein interactions. Curr. Opin. Struct. Biol. 50, 101–108 (2018).
pubmed: 29455055
doi: 10.1016/j.sbi.2017.12.011
Nagarajan, B., Holmes, S. G., Sankaranarayanan, N. V. & Desai, U. R. Molecular dynamics simulations to understand glycosaminoglycan interactions in the free- and protein-bound states. Curr. Opin. Struct. Biol. 74, 102356 (2022).
pubmed: 35306321
pmcid: 9189024
doi: 10.1016/j.sbi.2022.102356
Gama, C. I. et al. Sulfation patterns of glycosaminoglycans encode molecular recognition and activity. Nat. Chem. Biol. 2, 467–473 (2006).
pubmed: 16878128
doi: 10.1038/nchembio810
Habuchi, H., Habuchi, O. & Kimata, K. Sulfation pattern in glycosaminoglycan: does it have a code? Glycoconj. J. 21, 47–52 (2004).
pubmed: 15467398
doi: 10.1023/B:GLYC.0000043747.87325.5e
Shi, X. & Zaia, J. Organ-specific heparan sulfate structural phenotypes. J. Biol. Chem. 284, 11806–11814 (2009).
pubmed: 19244235
pmcid: 2673249
doi: 10.1074/jbc.M809637200
Zhang, X., Chen, L., Bancroft, D. P., Lai, C. K. & Maione, T. E. Crystal structure of recombinant human platelet factor 4. Biochemistry 33, 8361–8366 (1994).
pubmed: 8031770
doi: 10.1021/bi00193a025
Rubinson, K. A., Chen, Y., Cress, B. F., Zhang, F. & Linhardt, R. J. Heparin’s solution structure determined by small-angle neutron scattering. Biopolymers 105, 905–913 (2016).
pubmed: 27543274
pmcid: 5033728
doi: 10.1002/bip.22936
Khan, S., Gor, J., Mulloy, B. & Perkins, S. J. Semi-rigid solution structures of heparin by constrained X-ray scattering modelling: new insight into heparin-protein complexes. J. Mol. Biol. 395, 504–521 (2010).
pubmed: 19895822
doi: 10.1016/j.jmb.2009.10.064
Marcisz, M., Maszota-Zieleniak, M., Huard, B. & Samsonov, S. A. Advanced molecular dynamics approaches to model a tertiary complex APRIL/TACI with long glycosaminoglycans. Biomolecules 11, 1349 (2021).
Marcisz, M., Zacharias, M. & Samsonov, S. A. Modeling protein-glycosaminoglycan complexes: does the size matter? J. Chem. Inf. Model. 61, 4475–4485 (2021).
pubmed: 34494837
pmcid: 8479808
doi: 10.1021/acs.jcim.1c00664
Niu, C., Du, Y. & Kaltashov, I. A. Towards better understanding of the heparin role in NETosis: Feasibility of using native mass spectrometry to monitor interactions of neutrophil elastase with heparin oligomers. Int. J. Mass Spectrom. 463, 116550 (2021).
pubmed: 33692650
pmcid: 7939139
doi: 10.1016/j.ijms.2021.116550
Sachais, B. S. et al. Dynamic antibody-binding properties in the pathogenesis of HIT. Blood 120, 1137–1142 (2012).
pubmed: 22577175
pmcid: 3412334
doi: 10.1182/blood-2012-01-407262
Yeung, J., Li, W. & Holinstat, M. Platelet signaling and disease: targeted therapy for thrombosis and other related diseases. Pharmacol. Rev. 70, 526–548 (2018).
pubmed: 29925522
pmcid: 6013590
doi: 10.1124/pr.117.014530
Arepally, G. M. & Cines, D. B. Pathogenesis of heparin-induced thrombocytopenia. Transl. Res. 225, 131–140 (2020).
pubmed: 32417430
pmcid: 7487042
doi: 10.1016/j.trsl.2020.04.014
Warkentin, T. E. Platelet-activating anti-PF4 disorders: an overview. Semin. Hematol. 59, 59–71 (2022).
pubmed: 35512902
doi: 10.1053/j.seminhematol.2022.02.005
Arepally, G. M. & Padmanabhan, A. Heparin-Induced Thrombocytopenia: A Focus on Thrombosis. Arterioscler. Thromb. Vasc. Biol. 41, 141–152 (2021).
pubmed: 33267665
van Rees, D. J., Szilagyi, K., Kuijpers, T. W., Matlung, H. L. & van den Berg, T. K. Immunoreceptors on neutrophils. Semin. Immunol. 28, 94–108 (2016).
pubmed: 26976825
pmcid: 7129252
doi: 10.1016/j.smim.2016.02.004
Perdomo, J. et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat. Commun. 10, 1322 (2019).
pubmed: 30899022
pmcid: 6428879
doi: 10.1038/s41467-019-09160-7
Yang, Y., Ivanov, D. G. & Kaltashov, I. A. The challenge of structural heterogeneity in the native mass spectrometry studies of the SARS-CoV-2 spike protein interactions with its host cell-surface receptor. Anal. Bioanal. Chem. 413, 7205–7214 (2021).
pubmed: 34389878
pmcid: 8362873
doi: 10.1007/s00216-021-03601-3
Mócsai, A., Ruland, J. & Tybulewicz, V. L. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Rev. Immunol. 10, 387–402 (2010).
pubmed: 20467426
pmcid: 4782221
doi: 10.1038/nri2765
Huynh, A. et al. Development of a high-yield expression and purification system for platelet factor 4. Platelets 29, 249–256 (2018).
pubmed: 29172900
doi: 10.1080/09537104.2017.1378808
Sheridan, D., Carter, C. & Kelton, J. G. A diagnostic test for heparin-induced thrombocytopenia. Blood 67, 27–30 (1986).
pubmed: 3940551
doi: 10.1182/blood.V67.1.27.27
Lu, C. et al. OPLS4: improving force field accuracy on challenging regimes of chemical space. J. Chem. Theory Comput. 17, 4291–4300 (2021).
pubmed: 34096718
doi: 10.1021/acs.jctc.1c00302
Kaltashov, I. (Raw data files for the manuscript “Molecular architecture and platelet-activating properties of small immune complexes assembled on intact heparin and their possible involvement in heparin-induced thrombocytopenia” by Yang et al. Figshare. Dataset. https://doi.org/10.6084/m9.figshare.25148774.v3, (2024).