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Current Proteomics

Author(s): Vipul Upadhyay, Satinder Kaur, Rachna Hora and Prakash Chandra Mishra*

DOI: 10.2174/0115701646297476240408042556

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Investigating PI3P Binding with Plasmodium Falciparum HSP70 Proteins

Page: [14 - 24] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Plasmodium falciparum (P. falciparum) heat shock proteins (PfHSP70s) are an important class of molecules critically involved in parasite survival during stress. Interaction between the cytosolic PfHSP70-1 and a crucial lipid modulator, Phosphatidylinositol 3 Phosphate (PI3P), stabilizes the parasite Digestive Vacuole (DV) to facilitate hemoglobin trafficking and breakdown, in turn impacting parasite survival.

Methods: PI3P binding on PfHSP70-1 is facilitated by its C-terminal LID domain that controls substrate binding. PI3P and PfHSP70 homologs are amply expressed together in various subcellular compartments of the parasite, providing them with opportunities to interact and modulate biological processes.

Results: Here, we have identified and analyzed the PI3P binding pockets of all four PfHSP70s by using structural bioinformatics tools to understand their interaction with this lipid. Our results show that differently localized PfHSP70 homologs bind PI3P with variable affinity.

Conclusion: Analysis of these results has also helped to pinpoint specific residues on PfHSP70s that may be engaged in these interactions. The present study may, therefore, form the basis for designing interventions that hinder PfHSP70-PI3P interaction and influence parasite survival.

Graphical Abstract

[1]
Hartl, F.U.; Bracher, A.; Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature, 2011, 475(7356), 324-332.
[http://dx.doi.org/10.1038/nature10317] [PMID: 21776078]
[2]
Saibil, H. Chaperone machines for protein folding, unfolding and disaggregation. Nat. Rev. Mol. Cell Biol., 2013, 14(10), 630-642.
[http://dx.doi.org/10.1038/nrm3658] [PMID: 24026055]
[3]
Murshid, A.; Prince, T.L.; Lang, B.; Calderwood, S.K. Role of heat shock factors in stress-induced transcription. Methods Mol Biol., 2018, 1709, 23-34.
[http://dx.doi.org/10.1007/978-1-4939-7477-1_2]
[4]
Lindquist, S. The heat-shock response. Annu. Rev. Biochem., 1986, 55(1), 1151-1191.
[http://dx.doi.org/10.1146/annurev.bi.55.070186.005443] [PMID: 2427013]
[5]
Hu, C.; Yang, J.; Qi, Z.; Wu, H.; Wang, B.; Zou, F.; Mei, H.; Liu, J.; Wang, W.; Liu, Q. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm, 2022, 3(3), e161.
[http://dx.doi.org/10.1002/mco2.161] [PMID: 35928554]
[6]
Brocchieri, L.; Conway de Macario, E.; Macario, A.J.L. hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol. Biol., 2008, 8(1), 19.
[http://dx.doi.org/10.1186/1471-2148-8-19] [PMID: 18215318]
[7]
Behl, A.; Kumar, V.; Bisht, A.; Panda, J.J.; Hora, R.; Mishra, P.C. Cholesterol bound Plasmodium falciparum co-chaperone ‘PFA0660w’ complexes with major virulence factor ‘PfEMP1’ via chaperone ‘PfHsp70-x’. Sci. Rep., 2019, 9(1), 2664.
[http://dx.doi.org/10.1038/s41598-019-39217-y] [PMID: 30804381]
[8]
Behl, A.; Mishra, P.C. Structural insights into the binding mechanism of Plasmodium falciparum exported Hsp40-Hsp70 chaperone pair. Comput. Biol. Chem., 2019, 83, 107099.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.107099] [PMID: 31430682]
[9]
Daugaard, M.; Rohde, M.; Jäättelä, M. The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions. FEBS Lett., 2007, 581(19), 3702-3710.
[http://dx.doi.org/10.1016/j.febslet.2007.05.039] [PMID: 17544402]
[10]
Mayer, M.P.; Bukau, B. Hsp70 chaperones: Cellular functions and molecular mechanism. Cell. Mol. Life Sci., 2005, 62(6), 670-684.
[http://dx.doi.org/10.1007/s00018-004-4464-6] [PMID: 15770419]
[11]
Przyborski, J.M.; Diehl, M.; Blatch, G.L. Plasmodial HSP70s are functionally adapted to the malaria parasite life cycle. Front. Mol. Biosci., 2015, 2, 34.
[http://dx.doi.org/10.3389/fmolb.2015.00034] [PMID: 26167469]
[12]
Sharma, D.; Masison, D. Hsp70 structure, function, regulation and influence on yeast prions. Protein Pept. Lett., 2009, 16(6), 571-581.
[http://dx.doi.org/10.2174/092986609788490230] [PMID: 19519514]
[13]
Külzer, S.; Charnaud, S.; Dagan, T.; Riedel, J.; Mandal, P.; Pesce, E.R.; Blatch, G.L.; Crabb, B.S.; Gilson, P.R.; Przyborski, J.M. Plasmodium falciparum -encoded exported hsp70/hsp40 chaperone/co-chaperone complexes within the host erythrocyte. Cell. Microbiol., 2012, 14(11), 1784-1795.
[http://dx.doi.org/10.1111/j.1462-5822.2012.01840.x] [PMID: 22925632]
[14]
Shonhai, A.; Boshoff, A.; Blatch, G.L. The structural and functional diversity of Hsp70 proteins from Plasmodium falciparum. Protein Sci., 2007, 16(9), 1803-1818.
[http://dx.doi.org/10.1110/ps.072918107] [PMID: 17766381]
[15]
Balla, T. Phosphoinositides: Tiny lipids with giant impact on cell regulation. Physiol. Rev., 2013, 93(3), 1019-1137.
[http://dx.doi.org/10.1152/physrev.00028.2012] [PMID: 23899561]
[16]
Mayinger, P. Phosphoinositides and vesicular membrane traffic. Biochim Biophys Acta., 2012, 1821(8), 1104-1113.
[17]
Vaid, A.; Ranjan, R.; Smythe, W.A.; Hoppe, H.C.; Sharma, P. PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking. Blood, 2010, 115(12), 2500-2507.
[http://dx.doi.org/10.1182/blood-2009-08-238972] [PMID: 20093402]
[18]
Lu, K.Y.; Pasaje, C.F.A.; Srivastava, T.; Loiselle, D.R.; Niles, J.C.; Derbyshire, E. Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death. eLife., 2020, 9, e56773.
[19]
Mbengue, A.; Bhattacharjee, S.; Pandharkar, T.; Liu, H.; Estiu, G.; Stahelin, R.V.; Rizk, S.S.; Njimoh, D.L.; Ryan, Y.; Chotivanich, K.; Nguon, C.; Ghorbal, M.; Lopez-Rubio, J.J.; Pfrender, M.; Emrich, S.; Mohandas, N.; Dondorp, A.M.; Wiest, O.; Haldar, K. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature, 2015, 520(7549), 683-687.
[http://dx.doi.org/10.1038/nature14412] [PMID: 25874676]
[20]
McCallister, C.; Kdeiss, B.; Nikolaidis, N. HspA1A, a 70-kDa heat shock protein, differentially interacts with anionic lipids. Biochem. Biophys. Res. Commun., 2015, 467(4), 835-840.
[http://dx.doi.org/10.1016/j.bbrc.2015.10.057] [PMID: 26476215]
[21]
McCallister, C.; Kdeiss, B.; Oliverio, R.; Nikolaidis, N. Characterization of the binding between a 70-kDa heat shock protein, HspA1A, and phosphoinositides. Biochem. Biophys. Res. Commun., 2016, 472(1), 270-275.
[http://dx.doi.org/10.1016/j.bbrc.2016.02.103] [PMID: 26923070]
[22]
Amos, B.; Aurrecoechea, C.; Barba, M.; Barreto, A.; Basenko, E.Y.; Bażant, W.; Belnap, R.; Blevins, A.S.; Böhme, U.; Brestelli, J.; Brunk, B.P.; Caddick, M.; Callan, D.; Campbell, L.; Christensen, M.B.; Christophides, G.K.; Crouch, K.; Davis, K.; DeBarry, J.; Doherty, R.; Duan, Y.; Dunn, M.; Falke, D.; Fisher, S.; Flicek, P.; Fox, B.; Gajria, B.; Giraldo-Calderón, G.I.; Harb, O.S.; Harper, E.; Hertz-Fowler, C.; Hickman, M.J.; Howington, C.; Hu, S.; Humphrey, J.; Iodice, J.; Jones, A.; Judkins, J.; Kelly, S.A.; Kissinger, J.C.; Kwon, D.K.; Lamoureux, K.; Lawson, D.; Li, W.; Lies, K.; Lodha, D.; Long, J.; MacCallum, R.M.; Maslen, G.; McDowell, M.A.; Nabrzyski, J.; Roos, D.S.; Rund, S.S.C.; Schulman, S.W.; Shanmugasundram, A.; Sitnik, V.; Spruill, D.; Starns, D.; Stoeckert, C.J., Jr; Tomko, S.S.; Wang, H.; Warrenfeltz, S.; Wieck, R.; Wilkinson, P.A.; Xu, L.; Zheng, J. VEuPathDB: The eukaryotic pathogen, vector and host bioinformatics resource center. Nucleic Acids Res., 2022, 50(D1), D898-D911.
[http://dx.doi.org/10.1093/nar/gkab929] [PMID: 34718728]
[23]
Madeira, F.; Pearce, M.; Tivey, A.R.N.; Basutkar, P.; Lee, J.; Edbali, O.; Madhusoodanan, N.; Kolesnikov, A.; Lopez, R. Search and sequence analysis tools services from EMBL-EBI in 2022. Nucleic Acids Res., 2022, 50(W1), W276-W279.
[http://dx.doi.org/10.1093/nar/gkac240] [PMID: 35412617]
[24]
Jumper, J.; Evans, R.; Pritzel, A.; Green, T.; Figurnov, M.; Ronneberger, O.; Tunyasuvunakool, K.; Bates, R.; Žídek, A.; Potapenko, A.; Bridgland, A.; Meyer, C.; Kohl, S.A.A.; Ballard, A.J.; Cowie, A.; Romera-Paredes, B.; Nikolov, S.; Jain, R.; Adler, J.; Back, T.; Petersen, S.; Reiman, D.; Clancy, E.; Zielinski, M.; Steinegger, M.; Pacholska, M.; Berghammer, T.; Bodenstein, S.; Silver, D.; Vinyals, O.; Senior, A.W.; Kavukcuoglu, K.; Kohli, P.; Hassabis, D. Highly accurate protein structure prediction with AlphaFold. Nature, 2021, 596(7873), 583-589.
[http://dx.doi.org/10.1038/s41586-021-03819-2] [PMID: 34265844]
[25]
Laskowski, R.A.; MacArthur, M.W.; Moss, D.S.; Thornton, J.M. PROCHECK: A program to check the stereochemical quality of protein structures. J. Appl. Cryst., 1993, 26(2), 283-291.
[http://dx.doi.org/10.1107/S0021889892009944]
[26]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera—A visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[27]
Shapovalov, M.V.; Dunbrack, R.L., Jr A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions. Structure, 2011, 19(6), 844-858.
[http://dx.doi.org/10.1016/j.str.2011.03.019] [PMID: 21645855]
[28]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2023 update. Nucleic Acids Res., 2023, 51(D1), D1373-D1380.
[http://dx.doi.org/10.1093/nar/gkac956] [PMID: 36305812]
[29]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(1), 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[30]
Chen, J.H.; Linstead, E.; Swamidass, S.J.; Wang, D.; Baldi, P. ChemDB update—full-text search and virtual chemical space. Bioinformatics, 2007, 23(17), 2348-2351.
[http://dx.doi.org/10.1093/bioinformatics/btm341] [PMID: 17599932]
[31]
Eberhardt, J.; Santos-Martins, D.; Tillack, A.F.; Forli, S. AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J. Chem. Inf. Model., 2021, 61(8), 3891-3898.
[http://dx.doi.org/10.1021/acs.jcim.1c00203] [PMID: 34278794]
[32]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334] [PMID: 19499576]
[33]
Laskowski, R.A.; Swindells, M.B. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model., 2011, 51(10), 2778-2786.
[http://dx.doi.org/10.1021/ci200227u] [PMID: 21919503]
[34]
Iershov, A.; Nemazanyy, I.; Alkhoury, C.; Girard, M.; Barth, E.; Cagnard, N.; Montagner, A.; Chretien, D.; Rugarli, E.I.; Guillou, H.; Pende, M.; Panasyuk, G. The class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα. Nat. Commun., 2019, 10(1), 1566.
[http://dx.doi.org/10.1038/s41467-019-09598-9] [PMID: 30952952]
[35]
Nascimbeni, A.C.; Codogno, P.; Morel, E. Phosphatidylinositol-3-phosphate in the regulation of autophagy membrane dynamics. FEBS J., 2017, 284(9), 1267-1278.
[http://dx.doi.org/10.1111/febs.13987] [PMID: 27973739]
[36]
Zhao, K.; Zhou, G.; Liu, Y.; Zhang, J.; Chen, Y.; Liu, L.; Zhang, G. HSP70 family in cancer: Signaling mechanisms and therapeutic advances. Biomolecules, 2023, 13(4), 601.
[http://dx.doi.org/10.3390/biom13040601] [PMID: 37189349]
[37]
Steinfeld, N.; Lahiri, V.; Morrison, A.; Metur, S.P.; Klionsky, D.J.; Weisman, L.S. Elevating PI3P drives select downstream membrane trafficking pathways. Mol Biol Cell, 2021, 132(2), 143-156.
[38]
Ali, F.; Wali, H.; Jan, S.; Zia, A.; Aslam, M.; Ahmad, I.; Afridi, S.G.; Shams, S.; Khan, A. Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria. Malar. J., 2021, 20(1), 335.
[http://dx.doi.org/10.1186/s12936-021-03865-1] [PMID: 34344361]