Alexandre Gingras

Title(s)Assistant Adjunct Professor, Medicine
SchoolHealth Sciences
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    Université LavalB.Sc.1997Biochemistry
    Université LavalM.Sc.1998Cellular and Molecular Biology
    University of LeicesterPh.D.2005Infection, Immunity and Inflammation

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    Dr. Gingras's work focus on determining the three-dimensional structure of protein-protein complexes to better understand how they interact with each others. He is also working closely with biologists to test structure-guided mutant proteins that fail to interact with each others to better understand the role of the interactions in the development of certain diseases. Dr. Gingras's research falls into three distinct but overlapping areas: i) cell-extracellular matrix interactions, ii) cell-cell interactions, and iii) the complement system of immunity.

    The first focus is to understand the structure, function and dynamics of talin dependent integrin activation. They solved the structures of all 18 domains of talin and complexes with binding partners. Together they show that talin has evolved to regulate integrin activity, it couples the integrins to cytoskeletal actin and acts as a mechanosensitive protein.

    A second focus is to determine the molecular basis of Cerebral Cavernous Malformations (CCMs), an autosomal dominant disorder affecting 1:200 people that arises from a weakening of endothelial cell junctions. They used structural and biochemical approaches to investigate the interaction between CCM proteins (CCM1-3), which form part of a multi-protein complex localized at endothelial cell-cell junctions.

    Finally, their work on the complement system of immunity has been to determine the structure of key proteins that recognize pathogens and this has lead to a better understanding on how they function. Moreover, inadequate complement activation becomes cause of disease and their structural insights revealed a new focus for inhibitors.

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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    1. Gingras AR, Lagarrigue F, Cuevas MN, Valadez AJ, Zorovich M, McLaughlin W, Lopez-Ramirez MA, Seban N, Ley K, Kiosses WB, Ginsberg MH. Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem. J Cell Biol. 2019 Jun 03; 218(6):1799-1809. PMID: 30988001.
      View in: PubMed
    2. Lagarrigue F, Gingras AR, Paul DS, Valadez AJ, Cuevas MN, Sun H, Lopez-Ramirez MA, Goult BT, Shattil SJ, Bergmeier W, Ginsberg MH. Rap1 binding to the talin 1 F0 domain makes a minimal contribution to murine platelet GPIIb-IIIa activation. Blood Adv. 2018 Sep 25; 2(18):2358-2368. PMID: 30242097.
      View in: PubMed
    3. Sun H, Lagarrigue F, Gingras AR, Fan Z, Ley K, Ginsberg MH. Transmission of integrin ß7 transmembrane domain topology enables gut lymphoid tissue development. J Cell Biol. 2018 04 02; 217(4):1453-1465. PMID: 29535192.
      View in: PubMed
    4. Gingras AR, Puzon-McLaughlin W, Bobkov AA, Ginsberg MH. Structural Basis of Dimeric Rasip1 RA Domain Recognition of the Ras Subfamily of GTP-Binding Proteins. Structure. 2016 12 06; 24(12):2152-2162. PMID: 27839947.
      View in: PubMed
    5. de Kreuk BJ, Gingras AR, Knight JD, Liu JJ, Gingras AC, Ginsberg MH. Heart of glass anchors Rasip1 at endothelial cell-cell junctions to support vascular integrity. Elife. 2016 Jan 19; 5:e11394. PMID: 26780829; PMCID: PMC4733052.
    6. Marshall JE, Faraj BH, Gingras AR, Lonnen R, Sheikh MA, El-Mezgueldi M, Moody PC, Andrew PW, Wallis R. The Crystal Structure of Pneumolysin at 2.0 Å Resolution Reveals the Molecular Packing of the Pre-pore Complex. Sci Rep. 2015 Sep 03; 5:13293. PMID: 26333773; PMCID: PMC4558608.
    7. Venkatraman Girija U, Furze CM, Gingras AR, Yoshizaki T, Ohtani K, Marshall JE, Wallis AK, Schwaeble WJ, El-Mezgueldi M, Mitchell DA, Moody PC, Wakamiya N, Wallis R. Molecular basis of sugar recognition by collectin-K1 and the effects of mutations associated with 3MC syndrome. BMC Biol. 2015 Apr 17; 13:27. PMID: 25912189; PMCID: PMC4431178.
    8. Gunawan M, Venkatesan N, Loh JT, Wong JF, Berger H, Neo WH, Li LY, La Win MK, Yau YH, Guo T, See PC, Yamazaki S, Chin KC, Gingras AR, Shochat SG, Ng LG, Sze SK, Ginhoux F, Su IH. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear regulatory protein talin. Nat Immunol. 2015 May; 16(5):505-16. PMID: 25751747.
      View in: PubMed
    9. Okada H, Lai NC, Kawaraguchi Y, Liao P, Copps J, Sugano Y, Okada-Maeda S, Banerjee I, Schilling JM, Gingras AR, Asfaw EK, Suarez J, Kang SM, Perkins GA, Au CG, Israeli-Rosenberg S, Manso AM, Liu Z, Milner DJ, Kaufman SJ, Patel HH, Roth DM, Hammond HK, Taylor SS, Dillmann WH, Goldhaber JI, Ross RS. Integrins protect cardiomyocytes from ischemia/reperfusion injury. J Clin Invest. 2013 Oct; 123(10):4294-308. PMID: 24091324.
      View in: PubMed
    10. Venkatraman Girija U, Gingras AR, Marshall JE, Panchal R, Sheikh MA, Harper JA, Gál P, Schwaeble WJ, Mitchell DA, Moody PC, Wallis R. Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation. Proc Natl Acad Sci U S A. 2013 08 20; 110(34):13916-20. PMID: 23922389; PMCID: PMC3752233.
    11. Gingras AR, Puzon-McLaughlin W, Ginsberg MH. The structure of the ternary complex of Krev interaction trapped 1 (KRIT1) bound to both the Rap1 GTPase and the heart of glass (HEG1) cytoplasmic tail. J Biol Chem. 2013 Aug 16; 288(33):23639-49. PMID: 23814056; PMCID: PMC3745310.
    12. Goult BT, Xu XP, Gingras AR, Swift M, Patel B, Bate N, Kopp PM, Barsukov IL, Critchley DR, Volkmann N, Hanein D. Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation. J Struct Biol. 2013 Oct; 184(1):21-32. PMID: 23726984; PMCID: PMC3799832.
    13. Goult BT, Zacharchenko T, Bate N, Tsang R, Hey F, Gingras AR, Elliott PR, Roberts GC, Ballestrem C, Critchley DR, Barsukov IL. RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover. J Biol Chem. 2013 Mar 22; 288(12):8238-49. PMID: 23389036; PMCID: PMC3605642.
    14. Gingras AR, Ye F, Ginsberg MH. Reconstructing integrin activation in vitro. Methods Mol Biol. 2013; 1046:1-17. PMID: 23868579.
      View in: PubMed
    15. Gingras AR, Liu JJ, Ginsberg MH. Structural basis of the junctional anchorage of the cerebral cavernous malformations complex. J Cell Biol. 2012 Oct 01; 199(1):39-48. PMID: 23007647.
      View in: PubMed
    16. Bate N, Gingras AR, Bachir A, Horwitz R, Ye F, Patel B, Goult BT, Critchley DR. Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics. PLoS One. 2012; 7(4):e34461. PMID: 22496808.
      View in: PubMed
    17. Gingras AR, Girija UV, Keeble AH, Panchal R, Mitchell DA, Moody PC, Wallis R. Structural basis of mannan-binding lectin recognition by its associated serine protease MASP-1: implications for complement activation. Structure. 2011 Nov 09; 19(11):1635-43. PMID: 22078562.
      View in: PubMed
    18. Liu JJ, Stockton RA, Gingras AR, Ablooglu AJ, Han J, Bobkov AA, Ginsberg MH. A mechanism of Rap1-induced stabilization of endothelial cell--cell junctions. Mol Biol Cell. 2011 Jul 15; 22(14):2509-19. PMID: 21633110; PMCID: PMC3135476.
    19. Kopp PM, Bate N, Hansen TM, Brindle NP, Praekelt U, Debrand E, Coleman S, Mazzeo D, Goult BT, Gingras AR, Pritchard CA, Critchley DR, Monkley SJ. Studies on the morphology and spreading of human endothelial cells define key inter- and intramolecular interactions for talin1. Eur J Cell Biol. 2010 Sep; 89(9):661-73. PMID: 20605055; PMCID: PMC2958305.
    20. Gingras AR, Bate N, Goult BT, Patel B, Kopp PM, Emsley J, Barsukov IL, Roberts GC, Critchley DR. Central region of talin has a unique fold that binds vinculin and actin. J Biol Chem. 2010 Sep 17; 285(38):29577-87. PMID: 20610383; PMCID: PMC2937989.
    21. Goult BT, Gingras AR, Bate N, Barsukov IL, Critchley DR, Roberts GC. The domain structure of talin: residues 1815-1973 form a five-helix bundle containing a cryptic vinculin-binding site. FEBS Lett. 2010 Jun 03; 584(11):2237-41. PMID: 20399778; PMCID: PMC2887493.
    22. Goult BT, Bouaouina M, Elliott PR, Bate N, Patel B, Gingras AR, Grossmann JG, Roberts GC, Calderwood DA, Critchley DR, Barsukov IL. Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation. EMBO J. 2010 Mar 17; 29(6):1069-80. PMID: 20150896; PMCID: PMC2845276.
    23. Goult BT, Bate N, Anthis NJ, Wegener KL, Gingras AR, Patel B, Barsukov IL, Campbell ID, Roberts GC, Critchley DR. The structure of an interdomain complex that regulates talin activity. J Biol Chem. 2009 May 29; 284(22):15097-106. PMID: 19297334; PMCID: PMC2685691.
    24. Himmel M, Ritter A, Rothemund S, Pauling BV, Rottner K, Gingras AR, Ziegler WH. Control of high affinity interactions in the talin C terminus: how talin domains coordinate protein dynamics in cell adhesions. J Biol Chem. 2009 May 15; 284(20):13832-42. PMID: 19278997; PMCID: PMC2679484.
    25. Gingras AR, Ziegler WH, Bobkov AA, Joyce MG, Fasci D, Himmel M, Rothemund S, Ritter A, Grossmann JG, Patel B, Bate N, Goult BT, Emsley J, Barsukov IL, Roberts GC, Liddington RC, Ginsberg MH, Critchley DR. Structural determinants of integrin binding to the talin rod. J Biol Chem. 2009 Mar 27; 284(13):8866-76. PMID: 19176533; PMCID: PMC2659244.
    26. Ribeiro CH, López NC, Ramírez GA, Valck CE, Molina MC, Aguilar L, Rodríguez M, Maldonado I, Martínez R, González C, Troncoso R, Lavandero S, Gingras AR, Schwaeble W, Ferreira A. Trypanosoma cruzi calreticulin: a possible role in Chagas' disease autoimmunity. Mol Immunol. 2009 Mar; 46(6):1092-9. PMID: 19108895.
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    27. Srivastava J, Barreiro G, Groscurth S, Gingras AR, Goult BT, Critchley DR, Kelly MJ, Jacobson MP, Barber DL. Structural model and functional significance of pH-dependent talin-actin binding for focal adhesion remodeling. Proc Natl Acad Sci U S A. 2008 Sep 23; 105(38):14436-41. PMID: 18780792; PMCID: PMC2532973.
    28. Critchley DR, Gingras AR. Talin at a glance. J Cell Sci. 2008 May 01; 121(Pt 9):1345-7. PMID: 18434644.
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    29. Gingras AR, Basran J, Prescott A, Kriajevska M, Bagshaw CR, Barsukov IL. Crystal structure of the Ca(2+)-form and Ca(2+)-binding kinetics of metastasis-associated protein, S100A4. FEBS Lett. 2008 May 28; 582(12):1651-6. PMID: 18435928.
      View in: PubMed
    30. Ziegler WH, Gingras AR, Critchley DR, Emsley J. Integrin connections to the cytoskeleton through talin and vinculin. Biochem Soc Trans. 2008 Apr; 36(Pt 2):235-9. PMID: 18363566.
      View in: PubMed
    31. Goult BT, Gingras AR, Bate N, Roberts GC, Critchley DR, Barsukov IL. NMR assignment of the C-terminal actin-binding domain of talin. Biomol NMR Assign. 2008 Jun; 2(1):17-9. PMID: 19636914.
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    32. Gingras AR, Bate N, Goult BT, Hazelwood L, Canestrelli I, Grossmann JG, Liu H, Putz NS, Roberts GC, Volkmann N, Hanein D, Barsukov IL, Critchley DR. The structure of the C-terminal actin-binding domain of talin. EMBO J. 2008 Jan 23; 27(2):458-69. PMID: 18157087; PMCID: PMC2168396.
    33. Gingras AR, Vogel KP, Steinhoff HJ, Ziegler WH, Patel B, Emsley J, Critchley DR, Roberts GC, Barsukov IL. Structural and dynamic characterization of a vinculin binding site in the talin rod. Biochemistry. 2006 Feb 14; 45(6):1805-17. PMID: 16460027.
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    34. Patel B, Gingras AR, Bobkov AA, Fujimoto LM, Zhang M, Liddington RC, Mazzeo D, Emsley J, Roberts GC, Barsukov IL, Critchley DR. The activity of the vinculin binding sites in talin is influenced by the stability of the helical bundles that make up the talin rod. J Biol Chem. 2006 Mar 17; 281(11):7458-67. PMID: 16407302.
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    35. Gingras AR, Ziegler WH, Frank R, Barsukov IL, Roberts GC, Critchley DR, Emsley J. Mapping and consensus sequence identification for multiple vinculin binding sites within the talin rod. J Biol Chem. 2005 Nov 04; 280(44):37217-24. PMID: 16135522.
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    36. Fillingham I, Gingras AR, Papagrigoriou E, Patel B, Emsley J, Critchley DR, Roberts GC, Barsukov IL. A vinculin binding domain from the talin rod unfolds to form a complex with the vinculin head. Structure. 2005 Jan; 13(1):65-74. PMID: 15642262.
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    37. Papagrigoriou E, Gingras AR, Barsukov IL, Bate N, Fillingham IJ, Patel B, Frank R, Ziegler WH, Roberts GC, Critchley DR, Emsley J. Activation of a vinculin-binding site in the talin rod involves rearrangement of a five-helix bundle. EMBO J. 2004 Aug 04; 23(15):2942-51. PMID: 15272303; PMCID: PMC514914.
    38. Ferreira V, Valck C, Sánchez G, Gingras A, Tzima S, Molina MC, Sim R, Schwaeble W, Ferreira A. The classical activation pathway of the human complement system is specifically inhibited by calreticulin from Trypanosoma cruzi. J Immunol. 2004 Mar 01; 172(5):3042-50. PMID: 14978109.
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    39. Nauta AJ, Bottazzi B, Mantovani A, Salvatori G, Kishore U, Schwaeble WJ, Gingras AR, Tzima S, Vivanco F, Egido J, Tijsma O, Hack EC, Daha MR, Roos A. Biochemical and functional characterization of the interaction between pentraxin 3 and C1q. Eur J Immunol. 2003 Feb; 33(2):465-73. PMID: 12645945.
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    40. Nauta AJ, Trouw LA, Daha MR, Tijsma O, Nieuwland R, Schwaeble WJ, Gingras AR, Mantovani A, Hack EC, Roos A. Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur J Immunol. 2002 Jun; 32(6):1726-36. PMID: 12115656.
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