Ricin: Difference between revisions
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{{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]]. | |||
<StructureSection load='3rtj' size=' | See also [[Ricin: A toxic protein]]; [[Ricin: Structure and function]]. | ||
<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]])'> | |||
==Structure== | ==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 <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. | 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. | ||
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. | |||
==Mechanism of action== | ==Mechanism of action== | ||
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. | 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. | ||
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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]]. | 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]]. | ||
== Site of ricin modification of rRNA == | == Site of ricin modification of rRNA == | ||
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 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 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 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>. | 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> | |||
==3D structures of ricin== | |||
[[Ricin 3D structures]] | |||
==See Also== | ==See Also== | ||
* [[Ribosome]] | * [[Ribosome]] | ||
* [[Large Ribosomal Subunit of Haloarcula|Large Ribosomal Subunit]] | * [[Large Ribosomal Subunit of Haloarcula|Large Ribosomal Subunit]] | ||
* [[Translation]] | * [[Translation]] | ||
==References== | ==References== | ||
{{Reflist}} | {{Reflist}} | ||
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