In silico analysis of structural modifications in and around the integrin alphaIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia.
ITGA2B; Glanzmann thrombasthenia; genetic variants; in silico analysis; alphaIIb genu
Abstract :
[en] BACKGROUND: Studies on the inherited bleeding disorder, Glanzmann thrombasthenia (GT), have helped define the role of the alphaIIbbeta3 integrin in platelet aggregation. Stable bent alphaIIbbeta3 undergoes conformation changes on activation allowing fibrinogen binding and its taking an extended form. The alphaIIb genu assures the fulcrum of the bent state. Our goal was to determine how structural changes induced by missense mutations in the alphaIIb genu define GT phenotype. METHODS: Sanger sequencing of ITGA2B and ITGB3 in the index case followed by in silico modeling of all known GT-causing missense mutations extending from the lower part of the beta-propeller, and through the thigh and upper calf-1 domains. RESULTS: A homozygous c.1772A>C transversion in exon 18 of ITGA2B coding for a p.Asp591Ala substitution in an interconnecting loop of the lower thigh domain of alphaIIb in a patient with platelets lacking alphaIIbbeta3 led us to extend our in silico modeling to all 16 published disease-causing missense variants potentially affecting the alphaIIb genu. Modifications of structuring H-bonding were the major cause in the thigh domain although one mutation gave mRNA decay. In contrast, short-range changes induced in calf-1 appeared minor suggesting long-range effects. All result in severe to total loss of alphaIIbbeta3 in platelets. The absence of mutations within a key Ca2+-binding loop in the genu led us to scan public databases; three potential single allele variants giving major structural changes were identiffied suggesting that this key region is not protected from genetic variation. CONCLUSIONS: It appears that the alphaIIb genu is the object of stringent quality control to prevent platelets from circulating with activated and extended integrin.
Disciplines :
Genetics & genetic processes Hematology
Author, co-author :
Pillois, Xavier
PETERS, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > Service d'hématologie biologique et immuno-hématologie
Segers, Karin
Nurden, Alan T.
Language :
English
Title :
In silico analysis of structural modifications in and around the integrin alphaIIb genu caused by ITGA2B variants in human platelets with emphasis on Glanzmann thrombasthenia.
Publication date :
December 2018
Journal title :
Molecular Genetics and Genomic Medicine
eISSN :
2324-9269
Publisher :
Wiley, Hoboken, United States - New Jersey
Pages :
1-12
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Adair, B. D., & Yeager, M. (2002). Three-dimensional model of the human platelet integrin αIIbβ3 based on electron cryomicroscopy and x-ray crystallography. Proceedings of the National Academy of Sciences of the United States of America, 99, 14059–14064. https://doi.org/10.1073/pnas.212498199
Ballut, L., Sapay, N., Chautard, E., Imberty, A., & Ricard-Blum, S. (2013). Mapping of heparin/heparin sulfate binding sites on αvβ3 integrin by molecular docking. Journal of Molecular Recognition, 26, 76–85. https://doi.org/10.1002/jmr.2250
Blue, R., Li, J., Steinberger, J., Murcia, M., Filizola, M., & Coller, B. S. (2010). Effects of limiting extension at the alphaIIb genu on ligand binding to integrin alphaIIbbeta3. Journal of Biological Chemistry, 285, 17604–17613. https://doi.org/10.1074/jbc.M110.107763
Buitrago, C. L., Rendon, A., Liang, Y., Simeoni, I., Negri, A., Consortium, T., Filizola, M., Ouwehand, W. H., & Coller, B. S. (2015). 4151 αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia. Proceedings of the National Academy of Sciences of the United States of America, 112, E1898–E1907. https://doi.org/10.1073/pnas.1422238112
Carrell, N. A., Fitzgerald, L. A., Steiner, B., Erickson, H. P., & Phillips, D. R. (1985). Structure of human platelet membrane glycoproteins IIb and IIIa as determined by electron microscopy. Journal of Biological Chemistry, 260, 1743–1749.
Choi, W.-S., Rice, W. J., Stokes, D. L., & Coller, B. S. (2013). Three-dimensional reconstruction of intact human integrin αIIbβ3: New implications for activation-dependent ligand binding. Blood, 122, 4165–4171. https://doi.org/10.1182/blood-2013-04-499194
Coller, B. S. (2015). αIIbβ3: Structure and function. Journal of Thrombosis and Haemostasis, 13(Suppl 1), S17–S25. https://doi.org/10.1111/jth.12915
Coller, B. S., & Shattil, S. A. (2008). The GPIIb/IIIa (integrin αIIbβ3) odyssey: A technology-driven saga of a receptor with twists, turns, and even a bend. Blood, 112, 3011–3025. https://doi.org/10.1182/blood-2008-06-077891
D'Andrea, G., Colaizzo, D., Vecchione, G., Grandone, E., Di Minno, G., Margaglione, M., & Glanzmann's Thrombasthenia Italian Team (GLATIT). (2002). Glanzmann's thrombasthenia: Identiffication of 19 new mutations in 30 patients. Thrombosis and Haemostasis, 87, 1034–1042.
Essex, D. W. (2009). Redox control of platelet function. Antioxidants and Redox Signaling, 11, 1191–1225. https://doi.org/10.1089/ars.2008.2322
French, D., & Coller, B. S. (1997). Hematologically important mutations in Glanzmann thrombasthenia. Blood Cells, Molecules, & Diseases, 23, 39–51. https://doi.org/10.1006/bcmd.1997.0117
Fu, B., Yuan, X., Chen, F., Xia, K., & Fu, G. (2005). A naturally occurring mutation near the C terminus of the beta-propeller of alpha(IIb) impair the transport of aplha(IIb)beta3 complexes from the endoplasmic reticulum to the Golgi apparatus. Journal of Thrombosis and Haemostasis, 3, 1324–1327. https://doi.org/10.1111/j.1538-7836.2005.01386.x
George, J. N., Caen, J. P., & Nurden, A. T. (1990). Glanzmann's thrombasthenia: The spectrum of clinical disease. Blood, 75, 1383–1395.
Goguet, M., Narwani, T. J., Petermann, R., Jallu, V., & De Brevern, A. G. (2017). In silico analysis of Glanzmann variants of calf-1 domain of αIIbβ3 integrin revealed dynamic allosteric effect. Scientiffic Reports, 7, 8001. https://doi.org/10.1038/s41598-017-08408-w
Gonzalez-Manchon, C., Fernandez-Pinel, M., Arias-Salgado, E. G., Ferrer, M., Alvarez, M. V., Garcia-Munoz, S., … Parrilla, R. (1999). Molecular genetic analysis of a compound heterozygote for the glycoprotein (GP) IIb gene associated with Glanzmann thrombasthenia: Disruption of the 647-687 disulfide bridge in GPIIb prevents surface exposure of GPIIb-IIIa complexes. Blood, 93, 866–875.
Haghighi, A., Borhany, M., Ghazi, A., Edwards, N., Tabaksert, A., Haghighi, A., … Sayer, J. A. (2016). Glanzmann thrombasthenia in Pakistan: Molecular analysis and identiffication of novel mutations. Clinical Genetics, 89, 187–192. https://doi.org/10.1111/cge.12622
Herrero, J., Muffato, M., Beal, K., Fitzgerald, S., Gordon, L., Pignatelli, M., … Flicek, P. (2016). Ensembl comparative genomics resources. Database (Oxford) Feb 2016. pii:bav096. https://doi.org/10.1093/database/bav096
Horton, E. R., Byron, A., Askari, J. A., Ng, D. H. J., Millon-Frémillon, A., Robertson, J., … Humphries, M. H. (2015). Definition of a consensus integrin adhesome and its dynamics during adhesion complex disassembly. Nature Cell Biology, 17, 1577–1589. https://doi.org/10.1038/ncb3257
Hynes, R. O. (2002). Integrins: Bidirectional, allosteric signaling machines. Cell, 110, 673–687. https://doi.org/10.1016/S0092-8674(02)00971-6
Jallu, V., Dusseaux, M., & Kaplan, C. (2011). A new Ser472Asn Cab2(a+) polymorphism localized within the alphaIIb “thigh” domain is involved in neonatal thrombocytopenia. Transfusion, 51, 393–400. https://doi.org/10.1111/j.1537-2995.2010.02815.x
Jallu, V., Dusseaux, M., Panzer, S., Torchet, M. F., Hezard, N., Goudemand, J., … Kaplan, C. (2010). AlphaIIbbeta3 integrin: New allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function. Human Mutation, 31, 237–246. https://doi.org/10.1002/humu.21179
Kamata, T., Handa, M., Ito, S., Sato, Y., Ohtani, T., Kawai, Y., … Aiso, S. (2010). Structural requirements for activation in αIIbβ3 integrin. Journal of Biological Chemistry, 285, 38428–38437. https://doi.org/10.1074/jbc.M110.139667
Ley, K., Rivera-Nieves, J., Sandborn, W. J., & Shattil, S. (2016). Integrin-based therapeutics: Biological basis, clinical use and new drugs. Nature Reviews Drug Discovery, 15, 173–183. https://doi.org/10.1038/nrd.2015.10
Li, J., Su, Y., Xia, W., Qin, Y., Humphries, M. J., Vestweber, D., … Springer, T. A. (2017). Conformational equilibria and intrinsic affinities define integrin activation. EMBO Journal, 36, 629–645. https://doi.org/10.15252/embj.201695803
Mitchell, W. B., Li, J., French, D. L., & Coller, B. S. (2006). alphaIIbbeta3 biogenesis is controlled by engagement of alphaIIb in the calnexin cycle via the N15-linked glycan. Blood, 107, 2713–2719. https://doi.org/10.1182/blood-2005-07-2990
Mitchell, W. B., Li, J., Murcia, M., Valentin, N., Newman, P. J., & Coller, B. S. (2007). Mapping early conformational changes in αIIb and β3 during biogenesis reveals a potential mechanism for αIIbβ3 adopting its bent conformation. Blood, 109, 3725–3732. https://doi.org/10.1182/blood-2006-11-058420
Mitchell, W. B., Li, J. H., Singh, F., Michelson, A. D., Bussel, J., Coller, B. S., & French, D. L. (2003). Two novel mutations in the alphaIIb calcium-binding domains identiffy hydrophobic regions essential for alphaIIbbeta3 biogenesis. Blood, 101, 2268–2276. https://doi.org/10.1182/blood-2002-07-2266
Nelson, E. J., Li, J., Mitchell, W. B., Chandy, M., Srivastava, A., & Coller, B. S. (2005). Three novel β-propeller mutations causing Glanzmann thrombasthenia result in production of normally stable pro-alphaIIb, but variably impaired progression of pro-alphaIIbbeta3 from endoplasmic reticulum to Golgi. Journal of Thrombosis and Haemostasis, 3, 2773–2783. https://doi.org/10.1111/j.1538-7836.2005.01593.x
Nelson, E. J., Nair, S. C., Peretz, H., Coller, B. S., Seligsohn, U., Chandy, M., & Srivastava, A. (2006). Diversity of Glanzmann thrombasthenia in southern India: 10 novel mutations identiffied among 15 unrelated patients. Journal of Thrombosis and Haemostasis, 4, 1730–1737. https://doi.org/10.1111/j.1538-7836.2006.02066.x
Nurden, A. T., Fiore, M., Nurden, P., & Pillois, X. (2011). Glanzmann thrombasthenia: A review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models. Blood, 118, 5996–6005. https://doi.org/10.1182/blood-2011-07-365635
Nurden, A. T., & Pillois, X. (2017). ITGA2B and ITGB3 mutations associated with Glanzmann thrombasthenia. Platelets, Nov 10: 1–4. https://doi.org/10.1080/09537104.2017.1371291 (Epub ahead of print).
Nurden, A. T., Pillois, X., Fiore, M., Alessi, M.-C., Bonduel, M., Dreyfus, M., … Vinciguerra, C. (2015). Expanding the mutation spectrum of the αIIbβ3 integrin in Glanzmann thrombasthenia: Screening of the ITGA2B and ITGB3 genes in a large international cohort. Human Mutation, 36, 548–561. https://doi.org/10.1002/humu.22776
Peretz, H., Rosenberg, N., Landau, M., Usher, S., Nelson, E. J., Mor-Cohen, R., … Seligsohn, U. (2006). Molecular diversity of Glanzmann thrombasthenia in southern India: New insights into mRNA splicing and structure-function correlations of alphaIIbbeta3 integrin (ITGA2B, ITGB3). Human Mutation, 27, 359–369. https://doi.org/10.1002/humu.20304
Peterson, J. A., Gitter, M. L., Kanack, A., Curtis, B., McFarland, J., Bougie, D., & Aster, R. (2010). New low-frequency platelet glycoprotein polymorphism associated with neonatal alloimmune thrombocytopenia. Transfusion, 50, 324–333. https://doi.org/10.1111/j.1537-2995.2009.02438.x
Pillitteri, D., Pilgrimm, A. K., & Kirchmaier, C. M. (2010). Novel mutations in the GPIIb and GPIIIa genes in Glanzmann thrombasthenia. Transfusion Medicine and Hemotherapy, 37, 268–277.
de Rezende, F. F., Martins Lima, A., Niland, S., Wittig, I., Heide, H., Schröder, K., & Eble, J. A. (2012). Integrin α7β1 is a redox-regulated target of hydrogen peroxide in vascular smooth muscle cell adhesion. Free Radical Biology and Medicine, 53, 521–531. https://doi.org/10.1016/j.freeradbiomed.2012.05.032
Ruan, J., Peyruchaud, O., Alberio, L., Valles, G., Clemetson, K. J., Bourre, F., & Nurden, A. T. (1998). Double heterozygosity of the GPIIb gene in a Swiss patient with type I Glanzmann thrombasthenia. British Journal of Haematology, 105, 523–531.
Sandrock, K., Halimeh, S., Wiegering, V., Kappert, G., Sauer, K., Deeg, N., … Zieger, B. (2012). Homozygous point mutations in platelet glycoprotein ITGA2B gene as a cause of Glanzmann thrombasthenia in 2 families. Klinische Padiatrie, 224, 174–178.
Sandrock-Lang, K., Oldenburg, J., Wiegering, V., Halimeh, S., Santoso, S., Kurnik, K., … Zieger, B. (2015). Characterization of patients with Glanzmann thrombasthenia and identiffication of 17 novel mutations. Thrombosis and Haemostasis, 113, 782–791.
Santoro, C., Rago, A., Biondo, F., Conti, L., Pulcinelli, F., Laurenti, L., … Mazzucconi, M. G. (2010). Prevalence of allo-immunization anti-HLA and anti-integrin alphaIIbbeta3 in Glanzmann thrombasthenia patients. Haemophilia, 16, 805–812. https://doi.org/10.1111/j.1365-2516.2010.02230.x
Smagghe, B. J., Huang, P. S., Ban, Y. E., Baker, D., & Springer, T. A. (2010). Modulation of integrin activation by an entropic spring in the β-knee. Journal of Biological Chemistry, 285, 32954–32966. https://doi.org/10.1074/jbc.M110.145177
Takagi, J., Petre, B. M., Walz, T., & Springer, T. A. (2002). Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell, 110, 599–611. https://doi.org/10.1016/S0092-8674(02)00935-2
Tokgoz, H., Torun Ozkan, D., Caliskan, U., & Akar, N. (2015). Novel mutations of integrin αIIb and β3 genes in Turkish children with Glanzmann's thrombasthenia. Platelets, 26, 779–782. https://doi.org/10.3109/09537104.2014.998994
Vijapurkar, M., Ghosh, K., & Shetty, S. (2009). Novel mutations in GPIIb gene in Glanzmann's thrombasthenia from India. Platelets, 20, 35–40. https://doi.org/10.1080/09537100802434861
Wertz, D., Boveroux, P., Péters, P., Lenelle, J., & Franssen, C. (2011). Surgical resection of a sphenoid wing mengioma in a patient with Glanzmann thrombasthenia. Acta Anaesthesiologica Belgica, 62, 83–86.
Xiao, T., Takagi, J., Coller, B. S., Wang, J.-H., & Springer, T. A. (2004). Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature, 432, 59–67. https://doi.org/10.1038/nature02976
Xie, C., Shimaoka, M., Xiao, T., Schwab, P., Klickstein, L. B., & Springer, T. A. (2004). The integrin α sububit leg extends at a Ca2+-dependent epitope in the thigh/genu interface upon activation. Proceedings of the National Academy of Sciences of the United States of America, 101, 15422–15427. https://doi.org/10.1073/pnas.0406680101
Xiong, J.-P., Mahalingham, B., Alonso, J. L., Borrelli, L. A., Rui, X., Anand, S., … Arnaout, M. A. (2009). Crystal structure of the complete integrin alphaVbeta3 ectodomain plus an alpha/beta transmembrane fragment. Journal of Cell Biology, 186, 589–600. https://doi.org/10.1083/jcb.200905085
Xiong, J.-P., Stehle, T., Diefenbach, B., Zhang, R., Dunker, R., Scott, D. L., … Arnaout, M. A. (2001). Crystal structure of the extracellular segment of integrin αvβ3. Science, 294, 339–344. https://doi.org/10.1126/science.1064535
Yagi, M., Murray, J., Strand, K., Blystone, S., Interland, G., Suda, Y., & Sobel, M. (2012). Heparin modulates the conformation and signaling of platelet integrin αIIbβ3. Thrombosis Research, 129, 743–749. https://doi.org/10.1016/j.thromres.2011.11.054
Ye, F., Hu, G., Taylor, D., Ratnikov, B., Bobov, A. A., McLean, M. A., … Ginsberg, M. H. (2010). Recreation of the terminal events in physiological integrin activation. Journal of Cell Biology, 188, 157–173. https://doi.org/10.1083/jcb.200908045
Zhang, K., & Chen, J. F. (2012). The regulation of integrin function by divalent cations. Cell Adhesion and Migration, 6, 20–29. https://doi.org/10.4161/cam.18702
Zhu, J., Luo, B. H., Xiao, T., Zhang, C., Nishida, N., & Springer, T. A. (2008). Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Molecular Cell, 32, 849–861. https://doi.org/10.1016/j.molcel.2008.11.018
Zhu, J., Zhu, J., & Springer, T. A. (2013). Complete integrin headpiece opening in eight steps. Journal of Cell Biology, 201, 1053–1068.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.