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{{STRUCTURE_2r3d| PDB=2r3d  | SIZE=400| SCENE= |right|CAPTION=Castor bean ricin complex with acetamide and sulfate, [[2r3d]] }}
{{BAMBED
|DATE=May 14, 2013
|OLDID=1797961
|BAMBEDDOI=10.1002/bmb.20716
}}
'''Ricin''' is a potent cytotoxin that is synthesized in the endosperm cells of maturing seeds of the castor oil plant (''Ricinus communis'')<ref name="lord">PMID: 8119491</ref>. Ricin belongs to a small multi-gene family<ref name="montfort">PMID: 3558397</ref> that is composed of eight members. Ricin is classified as a type II heterodimeric Ribosome Inactivating Protein<ref name="lord" /> or RIPs.  For toxins in Proteopedia see [[Toxins]].


See also [[Ricin: A toxic protein]]; [[Ricin: Structure and function]].


==Introduction==
<StructureSection load='3rtj'  size='350' side='right' caption='Glycosylated ricin chain A (grey) and chain B (green) bound to dinucleotide APG (stick model) (PDB entry [[3rtj]])'>
'''Ricin''' is a potent cytotoxin that is synthesized in the endosperm cells of maturing Riccinus seeds(1). Ricin belongs to a small multi gene family(2) that is composed of eight members. It is also important to mention that Ricin is classified as a type II heterodimeric Ribosome Inactivatiing protein(1).  
==Structure==
Ricin is a heterodimer that consists of a 32 kilodalton A chain glycoprotein (light blue) linked by a <scene name='38/382952/Disulfide_bond_between_subunit/3'>disulfide bond</scene> to a 32 kilodalton <scene name='Sandbox_BCMB402_Ricin/B_subunit/1'>B chain</scene> glycoprotein<ref name="montfort" /> (green).
 
The <scene name='Sandbox_BCMB402_Ricin/A_subunit_secondary_structure/2'> A chain</scene> is an alpha/beta protein which contains eight alpha helices (pink) and eight beta sheets (yellow). It has three domains<ref name="Weston">PMID: 7990130</ref>.  <scene name='Sandbox_BCMB402_Ricin/Domain_1_of_a_subunit/2'>Domain 1 </scene> consists of a beta sheet containing both parallel and anti-parallel strands.  The <scene name='Sandbox_BCMB402_Ricin/Domain2_of_a_subunit/1'> second alpha helical domain </scene> makes up the core of the protein, and includes the active site.  The<scene name='Sandbox_BCMB402_Ricin/Domain3_of_a_subunit/1'> third domain</scene> interacts with the B chain, and contains a helix and two beta strands.
 
The '''A chain''' contains the active site that is responsible for inactivating the [[Ribosome]] via depurination.  RIPs have very diverse structures, containing only eight invariant residues<ref name = "lord"/>.  These <scene name='Sandbox_BCMB402_Ricin/Conserved_residues/2'>conserved residues</scene> are clustered in the active site.


==Structure==
The '''B chain''' is a lectin<ref name="lord" /> that <scene name='Sandbox_BCMB402_Ricin/Carbohydrate_binding/1'>binds</scene> to galactose-containing surface receptors.  Originally it was thought that the mode of action of Ricin poisoning was due to hemagglutination due to a closely related, co-isolating lectin, RCA.  
<scene name='Sandbox_180/Act1/1'>Ricin</scene> is a heterodimer that consists of a 32,000 Dalton A chain glycoprotein linked by a disulfide bond to a 32,000 Dalton B chain glycoprotein(2). The A chain enzyme is a globular protein with extensive secondary structure and a predominate active site(2); where the B chain is a lectin(2) that binds to galactose-containing surface receptors(3).  
__NOTOC__


==Physiology==
==Mechanism of action==
The mechanism deployed by Ricin to gain entry to a host cell uses the heterogenic properties given to the toxin. Firstly the toxin arranges itself in such a way where its B chain can easily interact with the host cells receptors, and once acknowledgement happens, the B chain can fascilitate transport of the A chain into the cytoplasm(2). This association between the A and B chain is essential for toxicity(2) without it the Ricin would not be able to gain access to the cells organelles rendering it useless. Once the A chain gains entry into the cytosol its mechanism for attack of the ribosome is depurination of a single endenosine residue in 28S Ribosomal RNA(3) and this inhibits protein synthesis
The mechanism deployed by Ricin to gain entry to a host cell involves the poison's heterogenic properties. First, the B subunit binds to two carbohydrates on the cell surface, either glycolipids or glycoproteins, which both terminate with galactose.  The interaction is facilitated by hydrogen bonds to <scene name='Sandbox_BCMB402_Ricin/B_chain_bind_lactose_1/2'>lysine 40 and asparagine 46</scene> in one domain<ref name = "Rutenber">PMID: 3561502</ref> and <scene name='Sandbox_BCMB402_Ricin/B_chain_bind_lactose_2/1'>asparagine 255</scene> in the other domain. Once bound, the ricin-glycoprotein complex is taken into the cells via endocytosis. This association between the A and B chain is essential for toxicity <ref name="montfort" /> without it the Ricin would not be able to gain access to the cell, rendering it useless<ref name = "rapak">PMID: 9108055</ref>.  The endocytotic pathway results in the cleavage of the disulfide bond linking the A and B chains. After cleavage, the A chain is released into the cytosol.


==3D structures of ricin==
Once the A chain gains into the cytosol, it depurinates a single adenosine residue in a highly conserved portion within the  [[Large Ribosomal Subunit of Haloarcula|large ribosomal subunit]]<ref name="rapak" /> of eukaryotes; in human, the large cytoplasmic ribosomal RNA is called the 28S ribosomal RNA because of its sedimentation properties during ultracentrifugation. The nucleotide depurinated is located within a specific, conserved loop referred to as the <nowiki>'</nowiki>sarcin-ricin loop<nowiki>'</nowiki>. Depurination of the single adenosine nucleotide by the toxin results in the inhibition of protein synthesis.


===Ricin A chain (RTA)===
The proposed mechanism of depurination utilizes the <scene name='Sandbox_BCMB402_Ricin/Conserved_residues/2'>conserved residues</scene> in the A chain.  The aromatic ring structures of the substrate adenosine stack with the aromatic side chains of <scene name='Sandbox_BCMB402_Ricin/Tyr_stacking/1'>two tyrosine residues</scene>, Tyr 80 and 123, above and below.  Hydrogen bonds form between the conserved arginine and a backbone carbonyl.  The depurination reaction is aided by the protonation of N3 by Arg 180 and by ion pairing to Glu 177.  A water molecule on the opposite side of the ribose is activated by hydrogen bonding to Arg 180.  The activated water attacks C1' of the ribose, releasing the adenine and depurinated RNA fragment.  This interferes with elongation factor binding to the ribosome, thus inhibiting [[translation|translation]].


[[1j1m]], [[1ift]], [[2aai]], [[1rtc]] – RTA<br />
== Site of ricin modification of rRNA ==
[[3lc9]], [[3mk9]], [[2vc4]], [[1uq4]], [[1uq5]], [[1obs]] – RTA (mutant)
Ricin removes an adenine from a specific portion of the 28S rRNA called the <scene name='Taylor_sandboxk_ricin_rRNA_modification_site/Sarcin-ricin_loop/1'>sacrin-ricin loop</scene>, or SRL. This <scene name='Taylor_sandboxk_ricin_rRNA_modification_site/Depurination/1'>depurination</scene> leads to reduced binding of [[elongation factors|elongation factors]] to the ribosome and reduced synthesis of proteins<ref name="holmbergnygard">PMID: 8648651</ref>.  It appears that binding of ricin chain A to the ribosome is mediated by binding to the ribosomal proteins and the ribosomal stalk, as binding to the naked rRNA occurs with lower affinity.<ref name="Chiou">PMID: 19019145</ref>.


===Ricin A chain binary complexes===
Ricin also triggers apoptosis  <ref name="Tesh">PMID: 22130961</ref>, though the exact pathway is a current research topic.  There is some evidence that it occurs via the B subunit <ref name="Yermakova">PMID: 22984492</ref>,  though there is also evidence that the protein synthesis inhibition may cause apoptosis <ref name="Jetzt">PMID: 22982239</ref>.
</StructureSection>


[[3px8]] – RTA preproricin + 7-carboxy-pterin<br />
==3D structures of ricin==
[[1br5]], [[1br6]] - RTA + pterin derivative<br />
[[Ricin 3D structures]]
[[3px9]] - RTA preproricin + furanylmethyl-carbamoyl-pterin<br />
[[3lc9]], [[3mk9]], [[2vc4]], [[1uq4]], [[1uq5]], [[1obs]] – RTA (mutant) <br />
[[3hio]] – RTA + tetranucleotide<br />
[[3ej5]], [[2il5]] – RTA pyrimidine derivative<br />
[[2p8n]], [[1ifs]] – RTA + adenine<br />
[[2pjo]], [[2r2x]] – RTA + urea derivative<br />
[[2r3d]] – RTA + acetamide<br />
[[2vc3]] - RTA (mutant) + acetate<br />
[[1il3]], [[2il4]], [[2il9]] – RTA + guanine derivative<br />
[[1ifu]], [[1fmp]] – RTA + formycin<br />
[[1obt]] - RTA (mutant) + AMP<br />
[[1apg]] – RTA + RNA


==See Also==
* [[Ribosome]]
* [[Large Ribosomal Subunit of Haloarcula|Large Ribosomal Subunit]]
* [[Translation]]


==References==
==References==
{{Reflist}}


1. Lord, Michael J., Roberts, Lynne M., Robertus, Jon D. Ricin: structure, mode of action, and some current applications. The FSEB journal. Vol 8. 1994.
[[Category: Topic Page]]
2. Ernst, Stephen R., Hamlin, Ron., Katsen, Betsy., Montfort, William., Monzingo, Arthur F., Robertus, Jon D., Rutenbur, Earl., Villafranca, Jesus E., Xuong, Nuyhen H. The Three Dimensional  Structure of Ricin at 2.8 Angstrom. The Journal of Biological Chemistry. Vol 262, No 11, pp. 5398-5403.1987.
[[Category:Featured in BAMBED]]
3. Falnes, Pal., Olsnes, Sjur., Rapak, Andrzej. Retrograde Transport of Mutant Ricin to the Endoplasmic Recticulum with subsequent translocation to Cytosol. Cell Biology, Vol 94, pp. 3783-3788. 1997.

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Andrea Gorrell, Douglas Read, David Canner, Michal Harel, Wayne Decatur, Alexander Berchansky, Ann Taylor, Jaime Prilusky, Joel L. Sussman, Angel Herraez
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