View source for Delta endotoxins

{{short description|Insecticide}}
{{Infobox protein family
| Symbol = Endotoxin_N
| Name = Delta endotoxin, N-terminal domain
| image = PDB 1ji6 EBI.jpg
| width = 
| caption = crystal structure of the insecticidal bacterial del endotoxin [[Cry3Bb1]] ''Bacillus thuringiensis''<ref name="Galitsky_2001">{{cite journal | vauthors = Galitsky N, Cody V, Wojtczak A, Ghosh D, Luft JR, Pangborn W, English L | title = Structure of the insecticidal bacterial delta-endotoxin Cry3Bb1 of ''Bacillus thuringiensis'' | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 57 | issue = Pt 8 | pages = 1101–1109 | date = August 2001 | pmid = 11468393 | doi = 10.1107/S0907444901008186 }}</ref>
| Pfam = PF03945
| Pfam_clan =  
| InterPro = IPR005639
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1dlc
| TCDB = 1.C.2
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Pfam_box
| Symbol = Endotoxin_M
| Name = Delta endotoxin, middle domain
| Pfam= PF00555
|Pfam_clan=CL0568
| InterPro= IPR015790
| SMART=
| Prosite =
| SCOP = 1dlc
| TCDB =  1.C.2
| OPM family= 
| OPM protein= 
| PDB=
}}
{{Infobox protein family
| class =collapsible collapsed
| Symbol = Endotoxin_mid
| Name = Delta endotoxin, middle domain, Cry2A and Cry18
| image = PDB 1i5p EBI.jpg
| width = 
| caption = insecticidal crystal protein cry2aa
| Pfam = PF09131
| Pfam_clan =  
| InterPro = IPR015214
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1i5p
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = Endotoxin_C
| Name = Delta endotoxin, C-terminal
| Pfam = PF03944
| Pfam_clan = CL0202 
| InterPro = IPR005638
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1dlc
| TCDB = 1.C.2
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = cd04085
}}
{{Pfam box|Name=Cytolytic delta-endotoxin Cyt1/2 |Symbol=CytB|Pfam=PF01338|InterPro=IPR001615|TCDB=1.C.71|SCOP=1cby}}

'''Delta endotoxins''' ('''δ-endotoxins''') are a family of [[pore-forming toxin]]s produced by ''[[Bacillus thuringiensis]]'' species of bacteria.  They are useful for their [[insecticide|insecticidal]] action and are the primary toxin produced by the genetically modified (GM) [[Bt maize|Bt maize/corn]] and other GM crops.  During [[spore]] formation the bacteria produce crystals of such proteins (hence the name '''Cry''' toxins) that are also known as '''parasporal bodies''', next to the [[endospore]]s; as a result some members are known as a '''parasporin'''. The '''Cyt''' (cytolytic) toxin group is another group of delta-endotoxins formed in the cytoplasm.  '''VIP toxins''' (vegetative insecticidal proteins) are formed at other stages of the life cycle.<ref>{{Cite book|chapter=Risk assessment and management—Environment| author=Roger Hull| title=Genetically Modified Plants| edition=second| date=2021|quote=Upon sporulation, ''B. thuringiensis'' forms proteinaceous insecticidal δ-endotoxins either in crystals (Cry toxins) or cytoplasmically (Cyt toxins), which are encoded by cry or cyt genes, respectively. When insects ingest toxin crystals, the enzymes in their digestive tract cause the toxin to become activated. The toxin binds to the insect’s gut membranes, forming a pore that results in swelling, cell lysis, and eventually killing the insect. ''B. thuringiensis'' also produces insecticidal proteins at other stages in its lifecycle, specifically the vegetative insecticidal proteins (VIPs)|display-authors=etal}}</ref>

== Mechanism of action ==
When an insect ingests these proteins, they are activated by [[proteolytic cleavage]]. The N-terminus is cleaved in all of the proteins and a [[C-terminal]] extension is cleaved in some members. Once activated, the endotoxin binds to the gut [[epithelium]] and causes [[cell lysis]] by the formation of [[Ion channel|cation-selective channel]]s, which leads to death.<ref name="Grochulski_1995">{{cite journal | vauthors = Grochulski P, Masson L, Borisova S, Pusztai-Carey M, Schwartz JL, Brousseau R, Cygler M | title = ''Bacillus thuringiensis'' CryIA(a) insecticidal toxin: crystal structure and channel formation | journal = Journal of Molecular Biology | volume = 254 | issue = 3 | pages = 447–464 | date = December 1995 | pmid = 7490762 | doi = 10.1006/jmbi.1995.0630 }}</ref><ref name="Galitsky_2001" />

For many years there was no clarity as to the relationship between [[aminopeptidase N]] and Bt toxins. Although AP-N does bind Cry proteins in vitro<ref name="Ferre-Rie-2002" /> (reviewed by Soberón et al. 2009<ref name="Soberon-et-al-2009">{{cite journal | vauthors = Soberón M, Gill SS, Bravo A | title = Signaling versus punching hole: How do ''Bacillus thuringiensis'' toxins kill insect midgut cells? | journal = Cellular and Molecular Life Sciences | volume = 66 | issue = 8 | pages = 1337–1349 | date = April 2009 | pmid = 19132293 | doi = 10.1007/s00018-008-8330-9 | publisher = [[Springer Science+Business Media|Springer]] | s2cid = 5928827 | pmc = 11131463 }}</ref> and Pigott & Ellar 2007<ref name="Pigott-Ellar-2007">{{cite journal | vauthors = Pigott CR, Ellar DJ | title = Role of receptors in ''Bacillus thuringiensis'' crystal toxin activity | journal = Microbiology and Molecular Biology Reviews | volume = 71 | issue = 2 | pages = 255–281 | date = June 2007 | pmid = 17554045 | doi = 10.1128/mmbr.00034-06 | publisher = [[American Society for Microbiology]] | pmc = 1899880 | s2cid = 13982571 }}</ref>),<ref name="Lopez-et-al-2013">{{cite journal | vauthors = Pardo-López L, Soberón M, Bravo A | title = ''Bacillus thuringiensis'' insecticidal three-domain Cry toxins: mode of action, insect resistance and consequences for crop protection | journal = FEMS Microbiology Reviews | volume = 37 | issue = 1 | pages = 3–22 | date = January 2013 | pmid = 22540421 | doi = 10.1111/j.1574-6976.2012.00341.x | publisher = [[Federation of European Microbiological Societies]] ([[Oxford University Press|OUP]]) | doi-access = free }}</ref> no cases of [[Bt resistance|resistance]] {{endash}} or even reduced in vitro binding {{endash}} due to AP-N structure alteration were known through 2002, and there was some doubt that the resistance mechanism was so straight forward. Indeed, Luo et al. 1997, Mohammed et al. 1996, and Zhu et al. 2000 ''positively'' found this to ''not'' occur in [[Lepidoptera]] examples.<ref name="Ferre-Rie-2002">{{cite journal | vauthors = Ferré J, Van Rie J | title = Biochemistry and genetics of insect resistance to ''Bacillus thuringiensis'' | journal = Annual Review of Entomology | volume = 47 | issue = 1 | pages = 501–533 | year = 2002 | pmid = 11729083 | doi = 10.1146/annurev.ento.47.091201.145234 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] }}</ref> Subsequently, however Herrero et al. 2005 showed correlation between nonexpression and Bt resistance,<ref name="Lopez-et-al-2013" /> and actual resistance was found in ''[[Helicoverpa armigera]]'' by Zhang et al. 2009,<ref name="Lopez-et-al-2013" /><ref name="Vachon-et-al-2012">{{cite journal | vauthors = Vachon V, Laprade R, Schwartz JL | title = Current models of the mode of action of ''Bacillus thuringiensis'' insecticidal crystal proteins: a critical review | journal = Journal of Invertebrate Pathology | volume = 111 | issue = 1 | pages = 1–12 | date = September 2012 | pmid = 22617276 | doi = 10.1016/j.jip.2012.05.001 | publisher = [[Academic Press]] ([[Elsevier]]) | bibcode = 2012JInvP.111....1V }}</ref> in ''[[Ostrinia nubilalis]]'' by Khajuria et al. 2011, and in ''[[Trichoplusia ni]]'' by Baxter et al. 2011 and Tiewsiri & Wang 2011 (also all Lepidoptera).<ref name="Lopez-et-al-2013" /> There continues to be confirmation that AP-Ns do not by themselves affect resistance in some cases, possibly due to sequential binding by the toxin being required to produce its effect. In this sequence each binding step is theoretically not indispensable, but if it occurs does contribute to the final pore formation result.<ref name="Vachon-et-al-2012" />

== Structure ==
The activated region of the delta toxin is composed of three distinct [[structural domain]]s: an [[N-terminal]] [[helical bundle]] domain ({{InterPro|IPR005639}}) involved in membrane insertion and pore formation; a [[beta-sheet]] central domain involved in receptor binding; and a C-terminal [[beta-sandwich]] domain ({{InterPro|IPR005638}}) that interacts with the N-terminal domain to form a channel.<ref name="Galitsky_2001" /><ref name="Grochulski_1995" />

== Types ==
''B. thuringiensis'' encodes many proteins of the delta endotoxin family ({{InterPro|IPR038979}}), with some strains encoding multiple types simultaneously.<ref>{{cite web |title= Pesticidal crystal protein (IPR038979) |url=http://www.ebi.ac.uk/interpro/entry/IPR038979/ | work = InterPro |access-date=12 April 2019}}</ref> A gene mostly found on [[plasmid]]s,<ref name="Dean_1984">{{cite journal | vauthors = Dean DH | title = Biochemical genetics of the bacterial insect-control agent ''Bacillus thuringiensis'': basic principles and prospects for genetic engineering | journal = Biotechnology & Genetic Engineering Reviews | volume = 2 | pages = 341–363 | year = 1984 | pmid = 6443645 | doi = 10.1080/02648725.1984.10647804 | doi-access = free }}</ref> delta-entotoxins sometimes show up in genomes of other species, albeit at a lower proportion than those found in ''B. thuringiensis''.<ref>{{cite web |title=Species: Pesticidal crystal protein (IPR038979) |url=http://www.ebi.ac.uk/interpro/entry/IPR038979/taxonomy | work = InterPro}}</ref> The gene names looks like <code>Cry3Bb</code>, which in this case indicates a Cry toxin of superfamily 3 family B subfamily b.<ref>{{cite web |title= ''Bacillus thuringiensis'' Toxin Nomenclature |url=http://www.btnomenclature.info/ | work = Bt toxin specificity database |access-date=12 April 2019}}</ref>

''Cry'' proteins that are interesting to cancer research are listed under a parasporin (PS) nomenclature in addition to the Cry nomenclature. They do not kill insects, but instead kill leukemia cells.<ref>{{cite journal | vauthors = Mizuki E, Park YS, Saitoh H, Yamashita S, Akao T, Higuchi K, Ohba M | title = Parasporin, a human leukemic cell-recognizing parasporal protein of ''Bacillus thuringiensis'' | journal = Clinical and Diagnostic Laboratory Immunology | volume = 7 | issue = 4 | pages = 625–634 | date = July 2000 | pmid = 10882663 | pmc = 95925 | doi = 10.1128/CDLI.7.4.625-634.2000 }}</ref><ref>{{cite journal | vauthors = Ohba M, Mizuki E, Uemori A | title = Parasporin, a new anticancer protein group from ''Bacillus thuringiensis'' | journal = Anticancer Research | volume = 29 | issue = 1 | pages = 427–433 | date = January 2009 | pmid = 19331182 | url = http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=19331182 }}</ref><ref>{{cite web | url = http://parasporin.fitc.pref.fukuoka.jp/list.html | title = List of Parasporins | work = Committee of Parasporin Classification and Nomenclature }} Accessed Jan 4, 2013</ref> The Cyt toxins tend to form their own group distinct from Cry toxins.<ref>{{cite web | first = Neil | last = Crickmore | name-list-style = vanc |title= Other Cry Sequences | url= http://www.lifesci.susx.ac.uk/home/Neil_Crickmore/Bt/othercry.pdf |access-date=12 April 2019}}</ref> Not all ''Cry'' {{emdash}} crystal-form {{emdash}} toxins directly share a common root.<ref>{{cite journal | vauthors = Crickmore N, Zeigler DR, Feitelson J, Schnepf E, Van Rie J, Lereclus D, Baum J, Dean DH | display-authors = 6 | title = Revision of the nomenclature for the ''Bacillus thuringiensis'' pesticidal crystal proteins | journal = Microbiology and Molecular Biology Reviews | volume = 62 | issue = 3 | pages = 807–813 | date = September 1998 | pmid = 9729610 | pmc = 98935 | doi = 10.1128/MMBR.62.3.807-813.1998 }}</ref> Examples of non-three-domain toxins that nevertheless have a ''Cry'' name include [[Cry34Ab1|Cry34/35Ab1]] and related beta-sandwich binary (''Bin''-like) toxins, [[Cry6Aa]], and many beta-sandwich parasporins.<ref name="Kelker2014">{{cite journal | vauthors = Kelker MS, Berry C, Evans SL, Pai R, McCaskill DG, Wang NX, Russell JC, Baker MD, Yang C, Pflugrath JW, Wade M, Wess TJ, Narva KE | display-authors = 6 | title = Structural and biophysical characterization of ''Bacillus thuringiensis'' insecticidal proteins Cry34Ab1 and Cry35Ab1 | journal = PLOS ONE | volume = 9 | issue = 11 | pages = e112555 | date = 2014-11-12 | pmid = 25390338 | pmc = 4229197 | doi = 10.1371/journal.pone.0112555 | doi-access = free | bibcode = 2014PLoSO...9k2555K }}</ref>

Specific delta-endotoxins that have been inserted with [[genetic engineering]] include Cry3Bb1 found in [[MON 863]] and Cry1Ab found in [[MON 810]], both of which are [[maize cultivar|maize/corn cultivar]]s. Cry3Bb1 is particularly useful because it kills Coleopteran insects such as the [[corn rootworm]], an activity not seen in other Cry proteins.<ref name="Galitsky_2001" /> Other common toxins include [[Cry2Ab]] and [[Cry1F]] in [[transgenic cotton|cotton]] and [[transgenic maize|maize/corn]].<ref name="Tabashnik_2013" /> In addition, [[Cry1Ac]] is effective as a vaccine adjuvant in humans.<ref name="Rodriguez-Monroy2010">{{cite journal | vauthors = Rodriguez-Monroy MA, Moreno-Fierros L | title = Striking activation of NALT and nasal passages lymphocytes induced by intranasal immunization with Cry1Ac protoxin | journal = Scandinavian Journal of Immunology | volume = 71 | issue = 3 | pages = 159–168 | date = March 2010 | pmid = 20415781 | doi = 10.1111/j.1365-3083.2009.02358.x | doi-access = free }}</ref>

Some insects populations have started to develop resistance towards delta endotoxin, with five resistant species found as of 2013. Plants with two kinds of delta endotoxins tend to make resistance happen slower, as the insects have to evolve to overcome both toxins at once. Planting non-Bt plants with the resistant plants will reduce the selection pressure for developing the toxin. Finally, two-toxin plants should not be planted with one-toxin plants, as one-toxin plants act as a stepping stone for adaption in this case.<ref name="Tabashnik_2013">{{cite journal | vauthors = Tabashnik BE, Brévault T, Carrière Y | title = Insect resistance to Bt crops: lessons from the first billion acres | journal = Nature Biotechnology | volume = 31 | issue = 6 | pages = 510–521 | date = June 2013 | pmid = 23752438 | doi = 10.1038/nbt.2597 | s2cid = 205278530 }}</ref>

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Bravo A, Gill SS, Soberón M | title = Mode of action of ''Bacillus thuringiensis'' Cry and Cyt toxins and their potential for insect control | journal = Toxicon | volume = 49 | issue = 4 | pages = 423–435 | date = March 2007 | pmid = 17198720 | pmc = 1857359 | doi = 10.1016/j.toxicon.2006.11.022 | bibcode = 2007Txcn...49..423B }}
* {{cite journal | vauthors = Pigott CR, Ellar DJ | title = Role of receptors in ''Bacillus thuringiensis'' crystal toxin activity | journal = Microbiology and Molecular Biology Reviews | volume = 71 | issue = 2 | pages = 255–281 | date = June 2007 | pmid = 17554045 | pmc = 1899880 | doi = 10.1128/MMBR.00034-06 }}
* {{cite journal | vauthors = Palma L, Muñoz D, Berry C, Murillo J, Caballero P | title = ''Bacillus thuringiensis'' toxins: an overview of their biocidal activity | journal = Toxins | volume = 6 | issue = 12 | pages = 3296–3325 | date = December 2014 | pmid = 25514092 | pmc = 4280536 | doi = 10.3390/toxins6123296 | doi-access = free }}
{{refend}}

== External links ==
* [http://www.epa.gov/oppbppd1/biopesticides/ingredients/factsheets/factsheet_006484.htm Cry3Bb1] at the ''[[United States Environmental Protection Agency]]''

{{Toxins}}

{{InterPro content|IPR015790}}
{{Authority control}}

{{DEFAULTSORT:Delta Endotoxin}}
[[Category:Protein domains]]
[[Category:Peripheral membrane proteins]]
[[Category:Bacterial toxins]]
[[Category:Crystals]]
[[Category:Proteins]]