Structural insights into host GTPase isoform selection by a family of bacterial GEF mimics
Open accessAbstract
The Escherichia coli type III effector Map belongs to a large family of bacterial virulence factors that activate host Rho GTPase signaling pathways through an unknown molecular mechanism. Here we report direct evidence that Map functions as a potent and selective guanine-nucleotide exchange factor (GEF) for Cdc42. The 2.3-A structure of the Map-Cdc42 complex revealed that Map mimics the GEF strategy of the mammalian Dbl family but has a three-dimensional architecture that is nearly identical to the bacterial GEF Salmonella spp. SopE. A comparative analysis between human and bacterial GEFs revealed a previously uncharacterized pairing mechanism between Map and the variable beta2-3 interswitch region of Cdc42. We propose a GTPase selection model that is experimentally validated by the preferential activation Rac1 and RhoA by the Shigella spp. effectors IpgB1 and IpgB2, respectively. These results significantly expand the repertoire of bacterial GEF mimics and unify a GEF selection mechanism for host GTPase substrates.
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Bacterial toxins or effectors mimicking GEF proteins, such as SopE from Salmonella and MAP from Escherichia coli, can interact with Cdc42 and activate it.
“Bacterial secretes toxins or effectors mimicking the GEF proteins, such as SopE (PDB: 1GZS) from Salmonella208 and MAP (PDB: 3GCG) from Escherichia coli,209 can interact with Cdc42 and activate it.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [209]
Human-microbiome protein-protein interactions promote GTPase activation.
“Figure 3 Human–microbiome PPIs promote GTPase activation.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [209]
Pathogen proteins can have surfaces that resemble host protein surfaces, allowing them to mimic and compete with host protein interactions.
“Mechanistically, pathogen proteins can have surfaces which resemble those of the host, allowing them to mimic and compete with host protein interactions (Figure 3).”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [209]
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Cites
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475 · see citing works
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,299 · see citing works
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
RHO GTPASES: Biochemistry and Biology
Jaffe, A. B., & Hall, A. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.020604.150721 · Cited by 3,009 · see citing works
The Guanine Nucleotide-Binding Switch in Three Dimensions
Vetter, I. R., & Wittinghofer, A. (2001) · Science · doi:10.1126/science.1062023 · Cited by 1,875 · see citing works
Burridge, K., & Wennerberg, K. (2004) · Cell · doi:10.1016/s0092-8674(04)00003-0 · Cited by 1,790 · see citing works
Hardt, W., Chen, L., Schuebel, K. E., Bustelo, X. R., & Galán, J. E. (1998) · Cell · doi:10.1016/s0092-8674(00)81442-7 · Cited by 811 · see citing works
Salmonella maintains the integrity of its intracellular vacuole through the action of SifA
Beuzón, C. R., Méresse, S., Unsworth, K. E., Ruiz‐Albert, J., Garvis, S., Waterman, S. R., Ryder, T. A., Boucrot, E., & Holden, D. W. (2000) · The EMBO Journal · doi:10.1093/emboj/19.13.3235 · Cited by 595 · see citing works
A Bacterial Guanine Nucleotide Exchange Factor Activates ARF on Legionella Phagosomes
Nagai, H., Kagan, J. C., Zhu, X., Kahn, R., & Roy, C. R. (2002) · Science · doi:10.1126/science.1067025 · Cited by 551 · see citing works
Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbloncogene product
Hart, M. J., Eva, A., Evans, T., Aaronson, S. A., & Cerione, R. A. (1991) · Nature · doi:10.1038/354311a0 · Cited by 425 · see citing works
SOLVE and RESOLVE: automated structure solution, density modification and model building
Terwilliger, T. C. (2003) · Journal of Synchrotron Radiation · doi:10.1107/s0909049503023938 · Cited by 406 · see citing works
Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1
Worthylake, D. K., Rossman, K. L., & Sondek, J. (2000) · Nature · doi:10.1038/35047014 · Cited by 355 · see citing works
Automated structure solution, density modification and model building
Terwilliger, T. C. (2002) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444902016438 · Cited by 285 · see citing works
Stein, M. A., Leung, K. Y., Zwick, M. B., del Portillo, F. G., & Finlay, B. B. (1996) · Molecular Microbiology · doi:10.1111/j.1365-2958.1996.tb02497.x · Cited by 283 · see citing works
Identification of a Bacterial Type III Effector Family with G Protein Mimicry Functions
Alto, N. M., Shao, F., Lazar, C. S., Brost, R. L., Chua, G., Mattoo, S., McMahon, S. A., Ghosh, P., Hughes, T. R., Boone, C. M., et al. (2006) · Cell · doi:10.1016/j.cell.2005.10.031 · Cited by 262 · see citing works
Self-citationTargeting of an enteropathogenic Escherichia coli (EPEC) effector protein to host mitochondria
Kenny, B., & Jepson, M. A. (2000) · Cellular Microbiology · doi:10.1046/j.1462-5822.2000.00082.x · Cited by 257 · see citing works
The Intracellular Fate of Salmonella Depends on the Recruitment of Kinesin
Boucrot, E., Henry, T., Borg, J., Gorvel, J., & Méresse, S. (2005) · Science · doi:10.1126/science.1110225 · Cited by 237 · see citing works
Rossman, K. L., Worthylake, D. K., Snyder, J. T., Siderovski, D. P., Campbell, S. L., & Sondek, J. (2002) · The EMBO Journal · doi:10.1093/emboj/21.6.1315 · Cited by 222 · see citing works
Isolation of a new human oncogene from a diffuse B-cell lymphoma
Eva, A., & Aaronson, S. A. (1985) · Nature · doi:10.1038/316273a0 · Cited by 212 · see citing works
Structural basis for the selective activation of Rho GTPases by Dbl exchange factors
Snyder, J. T., Worthylake, D. K., Rossman, K. L., Betts, L., Pruitt, W. M., Siderovski, D. P., Der, C. J., & Sondek, J. (2002) · Nature Structural Biology · doi:10.1038/nsb796 · Cited by 209 · see citing works
[1] Purification of recombinant Rho/Rac/G25K from Escherichia coli
Self, A. J., & Hall, A. K. (1995) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(95)56003-3 · Cited by 192 · see citing works
Kenny, B., Ellis, S., Leard, A. D., Warawa, J., Mellor, H., & Jepson, M. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.02952.x · Cited by 184 · see citing works
García‐Mata, R., & Burridge, K. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.11.004 · Cited by 166 · see citing works
Ohlson, M. B., Huang, Z., Alto, N. M., Blanc, M.-P., Dixon, J. E., Chai, J., & Miller, S. I. (2008) · Cell Host & Microbe · doi:10.1016/j.chom.2008.08.012 · Cited by 164 · see citing works
Self-citationShigella IpgB1 promotes bacterial entry through the ELMO–Dock180 machinery
Handa, Y., Suzuki, M., Ohya, K., Iwai, H., Ishijima, N., Koleske, A. J., Fukui, Y., & Sasakawa, C. (2006) · Nature Cell Biology · doi:10.1038/ncb1526 · Cited by 150 · see citing works
Structure and mutagenesis of the Dbl homology domain
Aghazadeh, B., Zhu, K., Kubiseski, T. J., Liu, G. A., Pawson, T., Zheng, Y., & Rosen, M. K. (1998) · Nature Structural Biology · doi:10.1038/4209 · Cited by 145 · see citing works
Structural basis for the reversible activation of a Rho protein by the bacterial toxin SopE
Buchwald, G., Friebel, A., Galán, J. E., Hardt, W., Wittinghofer, A., & Scheffzek, K. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf329 · Cited by 135 · see citing works
Alto, N. M., Weflen, A. W., Rardin, M. J., Yarar, D., Lazar, C., Tonikian, R., Koller, A., Taylor, S. S., Boone, C., Sidhu, S., et al. (2007) · Journal of Cell Biology · doi:10.1083/jcb.200705021 · Cited by 134 · see citing works
Self-citationBrumell, J. H., Tang, P., Mills, S. D., & Finlay, B. B. (2001) · Traffic · doi:10.1034/j.1600-0854.2001.20907.x · Cited by 125 · see citing works
IpgB1 Is a Novel Shigella Effector Protein Involved in Bacterial Invasion of Host Cells
Ohya, K., Handa, Y., Ogawa, M., Suzuki, M., & Sasakawa, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m502509200 · Cited by 107 · see citing works
Amor, J. C., Swails, J. L., Zhu, X., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410820200 · Cited by 104 · see citing works
Molecular basis for Rac1 recognition by guanine nucleotide exchange factors.
(2001) · Nature Structural Biology · doi:10.1038/nsb719 · Cited by 93 · see citing works
Derewenda, U., Oleksy, A., Stevenson, A. S., Korczynska, J., Dauter, Z., Somlyo, A. P., Otlewski, J., Somlyo, A. V., & Derewenda, Z. S. (2004) · Structure · doi:10.1016/j.str.2004.09.003 · Cited by 90 · see citing works
Subversion of actin dynamics by EspM effectors of attaching and effacing bacterial pathogens
Arbeloa, A., Bulgin, R. R., MacKenzie, G., et al. (2008) · Cellular Microbiology · doi:10.1111/j.1462-5822.2008.01136.x · Cited by 76 · see citing works
[9] Guanine nucleotide exchange catalyzed by dbl oncogene product
Zheng, Y., Hart, M. J., & Cerione, R. A. (1995) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(95)56011-4 · Cited by 75 · see citing works
Simpson, N., Shaw, R. K., Crepin, V. F., et al. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05109.x · Cited by 74 · see citing works
Hachani, A., Biskri, L., Rossi, G., Marty, A. J., Ménard, R., Sansonetti, P. J., Parsot, C., Nhieu, G. T. V., Bernardini, M. L., & Allaoui, A. (2007) · Microbes and Infection · doi:10.1016/j.micinf.2007.11.011 · Cited by 63 · see citing works
The mechanisms used by enteropathogenicEscherichia colito control filopodia dynamics
Berger, C. N., Crepin, V. F., Jepson, M. A., et al. (2008) · Cellular Microbiology · doi:10.1111/j.1462-5822.2008.01254.x · Cited by 61 · see citing works
Larger than Dbl: new structural insights into RhoA activation
Rossman, K. L., & Sondek, J. (2005) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2005.02.002 · Cited by 49 · see citing works
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LaRock, D. L., Chaudhary, A., & Miller, S. I. (2015) · Nature Reviews Microbiology · doi:10.1038/nrmicro3420 · Cited by 502 · see citing works
AlphaFold, Artificial Intelligence (AI), and Allostery
Nussinov, R., Zhang, M., Liu, Y., & Jang, H. (2022) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.2c04346 · Cited by 190 · see citing works
- Authors
- Huang, Z., Sutton, S. E., Wallenfang, A. J., Orchard, R. C., Wu, X., Feng, Y., Chai, J., & Alto, N. M.
- Affiliations
- National Institute of Biological Sciences, Beijing (CN)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Chai, Jijie
- Alto, Neal M
- Venue
- Nature Structural & Molecular Biology
- Published
- 2009-07-20
- Volume
- 16
- Issue
- 8
- Pages
- 853-860
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC5130228
- OpenAlex
- W2124232374
- Cited by
- 139
- References
- 40
- Citations by year
- 2025: 6 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 2 · 2020: 8 · 2019: 2 · 2018: 7 · 2017: 10 · 2016: 12 · 2015: 8 · 2014: 9 · 2013: 15 · 2012: 8
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI083359)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Pathogenic Bacteria Studies
- Keywords
- Cdc42, guanine nucleotide exchange factor, Rho GTPase signaling, bacterial virulence factors, SopE, protein complex structure, Rac1 activation, RhoA activation, cytoskeletal dynamics
- MeSH terms
- Amino Acid Sequence, Binding Sites, Binding, Competitive, Cell Line, Crystallization, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Recombinant Fusion Proteins, Transfection, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Guanine Nucleotide Exchange Factors, rho GTP-Binding Proteins, cdc42 GTP-Binding Protein, Escherichia coli Proteins, Green Fluorescent Proteins
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