Ricin: Difference between revisions

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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 	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.
-Once the A chain gains into the cytosol, it depurinates[[Ribosome|ribosome]] 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>; the loop is critical for binding [[elongation factors|elongation factors]] during [[Translation|translation]] of messenger RNA to protein <ref name="holmbergnygard">PMID: 8648651</ref>. Depurination of the single adenosine nucleotide by the toxin results in the inhibition of protein synthesis.
+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.
 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]].
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 == Site of ricin modification of rRNA ==
 <Structure load='3u5d' size='400' side='left' caption='ribosomal RNA from Yeast(PDB entry [[3u5d]])' scene=''>
-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 to the ribosome and reduced synthesis of proteins.  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 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>.