Selenocysteine and selenoproteins

Wait a Sec! I thought U said this was #20DaysOfAminoAcids?! I know this is supposed to be #20DaysOfAminoAcids, because there are 20 (common) proteinogenic amino acids (protein letters) that can be genetically encoded (as opposed to changed after the fact), but there’s actually a 21st - selenocysteine. It looks like cysteine, but with selenium instead of sulfur. Sulfur vs. selenium may not seem like a big deal, but it matters a lot when there are electrons to steal! And it might be rare, but Selenium (Se)’s chemical properties can imbue electron give-take-ing abilities to proteins, allowing our body’s natural antioxidant system to protect us from high-energy reactive oxygen species (ROS). And selenocysteine is special in another way - it’s able to “fool” our “foolproof” protein-making machinery into adding it instead of stopping.  
 
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Proteins (molecular machines) are made up up of chains of building block “letters” called amino acids that are like charm bracelets. Amino acids have a generic backbone (chain link) that allows any amino acid to connect to any other amino acid as well as a unique side chain “charm” that sticks out. These charms have different chemical properties that allow them to interact in different ways w/one another (important for the protein to fold properly) & with other molecules (important for intracellular interactions). 
 
Over the past few weeks, we saw the 20 “usual” amino acid charms. We saw how there could be some modifications made to them after they’re already in proteins. Since the process of protein-making is called translation, we call such modifications “post-translational modifications” and they include things like: phosphorylation (adding a negatively-charged phosphate group (phosphate surrounded by 4 oxygens) - typically to serine (Ser, S), threonine (Thr, T), or tyrosine (Tyr, Y)); methylation (adding a -CH₃ group (often to (Lys, K)); hydroxylation (adding an -OH group, often to proline (Pro, P) or Lys) and glycosylation (adding a sugar chain - often to asparagine (Asn, N)). 
 
But all of those “special” amino acids come from changing the charms after the bracelet’s made - they’re not “spelled for” in the mRNA instructions, where amino acids are “spelled” in 3-letter RNA words called codons and, during translation, transfer RNAs (tRNAs) with matching anticodons on one part and the corresponding amino acid hooked up to another part bring them to be added to a growing peptide chain in a protein-making complex called the ribosome. 
 
There are multiple quality control steps to make sure 1) the right amino acid is attached to the right tRNA and 2) the right tRNA binds to the right codon in the mRNA. Yet, somehow, selenocysteine is able to trick this “foolproof” system… unlike the “special” amino acids we talked about before, like phosphorylated serine (phosphoserine), SELENOCYSTEINE (abbreviated Sec or U), is “original” - it’s added as the bracelet’s being made (translated) BUT it doesn’t have it’s own word. Instead, it hides a “secret message,” a stem-loop structure (named a SECIS element) in the “footnotes” (3’ untranslated region (UTR)) of the mRNA which tells the protein-making machinery that, in this particular protein, one of the words for stop (UGA) really spells selenocysteine. Thus, when the ribosome reaches that UGA, Sec-incorporating machinery is recruited and, instead of binding a release factor and cutting off the peptide, the ribosome adds Sec & keeps going along. 
 
Selenocysteine is able to sneak in - but it sure isn’t easy! It takes a lot of different molecular players working together. We’ll talk more about how it pulls it off later, but first I want to talk about why our bodies invest all that effort and energy - especially given that selenocysteine-containing proteins (selenoproteins) are rare in numbers terms - humans only have 25 selenocysteine-containing proteins (selenoproteins) as far as we know, compared to at lease 20,000 different total proteins. So why are we celebrating selenocysteine?  
 
Selonocysteine (Sec, U) & cysteine (Cys, C) - sounds like they should be similar… Indeed they are similar BUT they’re also subtly, importantly, different. And that difference comes from the difference between sulfur (S) and selenium (Se). That’s the only thing that’s different between them atom-wise. Cys’ side chain is a -CH₂-SH group, whereas Sec has a -CH₂-SeH group. -SH (what Cys has) is called a THIOL (it’s alcohol’s (-OH) sulfur CYSter). And -SeH (what Sec has) is called a SELENOL. We’ll talk more about the bigger picture of this later, but first I want to talk about the much smaller picture… yup, I’m talking the subatomic picture. 
 
The difference between Cys and Sec is a single atom (an atom of the element sulfur vs an atom of the element selenium).

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