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  • Ok, roll it.

  • Know what this is? It's the longest word in the world.

  • Like, anywhere, in any language, ever.

  • More than 189,000 letters.

  • If you were to write it down, though I don't know why you would, it'd fill up more than

  • 100 pages!

  • And if you could actually say it without, like, breaking your face, it'd take about

  • FIVE hours!

  • So what the frick is this word?

  • It's the name of the longest known protein on earth. And it's actually in you right now.

  • Because of its enormous size, it was given the nickname Titin by scientists.

  • And that's with two i's.

  • It's a protein that helps give some of the springiness to your muscles.

  • Today we're going to be talking about DNA and how it, along with three versions of its

  • cousin RNA, unleash chemical kung fu to synthesize proteins just like this.

  • This is going to take a while to explain, so how about if we make ourselves some hot pockets.

  • Mmmm, my favorite. Ham and cheese.

  • Every time I take a bite I wonder, how do they do it?

  • How do they pack exactly the same flavor into every foil-cardboard wrapped foodish item?

  • Clearly there has got to be some super secret instruction manual kept in a location known

  • to only two people.

  • And since I'm talking about biology here, that brings up a related question:

  • How did I get built from the DNA instructions and biological molecules we've been talking about?

  • Today, that's what I'm going to do. Not actually make hot pockets, or a person.

  • But I'm going to be talking about DNA transcription and translation

  • which is how we get made into the delicious things we are today.

  • Though hopefully none of us know how delicious people are.

  • Animals, plants, and hot pockets are really nothing more than salty water, carbohydrates,

  • fats, and protein, combined in precise proportions following very explicit instructions.

  • Let's say I want to make my own hot pocket. I would have to:

  • 1) break into the lair of the Hot Pocket Company holding the secret manual

  • 2) read the instructions on how to make the machinery to produce the hot pocket and the

  • proportions of the ingredients

  • 3) quickly write down that information in shorthand before I get caught by the hot pocket police

  • 4) go home and follow the instructions to build the machinery and mix the ingredients

  • until I have a perfect hot pocket. That's how we get us.

  • Very simply, inside a cell's nucleus, the DNA instruction manual is copied gene by gene

  • by transcription onto a kind of RNA

  • then taken out of the lair where the instructions are followed, by the process of translation

  • to assemble amino acid strings into polypeptides or proteins that make up all kinds of stuff

  • from this titin down here to the keratin in my hair.

  • But most of the polypeptides that get made aren't structural proteins like hair, they're enzymes

  • which go on to act like the assembly machinery, breaking down and building and combining carbohydrates

  • and lipids and proteins that make up variations of cell material.

  • So enzymes are just like whatever ingenious machinery 'they' use at the factory to make this.

  • Let's start in the lair -- I mean the nucleus.

  • The length of DNA that we're going to transcribe onto an RNA molecule is called our transcription unit.

  • Let's say, in today's example, that it's going to include the gene that transcribes

  • for our friend titin

  • which, in humans at least, occurs on Chromosome 2.

  • Now each transcription unit has a sequence just above it in the strand

  • and that's called "upstream"

  • biologists call that "upstream" on the strand

  • And that sequence defines where the transcription unit is going to begin.

  • This special sequence is the promoter, and it almost always contains a sequence of two

  • of the four nitrogenous bases we discussed in our last episode: adenine (A), thymine (T)

  • cytosine (C) and guanine (G).

  • Specifically, the promoter is a really simple repetition

  • we've got thymine, adenine, thymine, adenine, and then A-A-A.

  • And on the other side: ATATTTT. Because you know how this works, right!?

  • This is called the TATA box. It's nearly universal and helps our enzyme figure out where to bind to the strand.

  • Now, you'll remember from our episode about DNA structure that DNA strands run in one

  • of two directions

  • depending on which end of the strand is free and which end has a phosphate bond.

  • One direction is 5 prime-3 prime, and the other is 3 prime-5 prime.

  • In this case, upstream means toward the 3 prime end and downstream means toward 5 prime.

  • So the first enzyme in this process is RNA polymerase, and it copies the DNA sequence

  • downstream of the TATA box

  • that's towards the 5' end and copies it into a similar type of language:

  • messenger RNA [mRNA].

  • Quick aside: So you'll notice that to read the DNA in order to make enzymes we need an

  • enzyme in the first place.

  • So it kind of gets "chicken vs egg" here.

  • We need the enzyme to make the DNA and the DNA to make the enzyme.

  • So, where did RNA polymerase come from if we haven't made it yet!?

  • What an excellent question! It turns out all of these basic necessities get handed down

  • from Mom.

  • She packed quite a bit more into her egg cell than just her DNA so we had a healthy start.

  • So, thanks Mom!

  • So the RNA polymerase binds to the DNA at that TATA box, and begins to unzip the double-helix.

  • Working along the DNA chain, the enzyme reads the nitrogenous bases, those are the letters

  • and helps the RNA version of the nitrogenous bases floating around in the nucleus find their match.

  • Now as you ALSO might recall from our previous episode

  • nitrogenous bases only have one counterpart that they can bond with.

  • But RNA, which is the pink one here, doesn't have thymine like DNA does

  • which is the green and the blue.

  • Instead it has uracil (U), so U appears here in T's place as the partner to adenine.

  • As it moves, the RNA polymerase re-zips the DNA behind it and lets our new strand of messenger

  • RNA peel away.

  • Eventually, the RNA polymerase reaches another sequence downstream, called a termination

  • signal, that triggers it to pull off.

  • Now, some finishing touches before this info can safely leave the lair.

  • First, a special type of guanine (G) is added to the 5-prime end

  • that's the first part of the mRNA we copied

  • and this is called the 5' cap.

  • On the other end, it looks like I fell asleep with my finger on the A key of my keyboard

  • but another enzyme added about 250 adenines on the 3' end.

  • This is called the poly-A tail.

  • These caps on either end of the RNA package make it easier for the mRNA to leave the nucleus

  • and they also help protect it from degradation from passing enzymes, while making it easier

  • to connect with other organelles later on.

  • But that's still not the end of it. As if to try to confuse me to protect the secret

  • hotpocket recipe

  • the original recipe book also contains lots of extra, misleading information.

  • So just before leaving the nucleus, that extra information gets cut out of the RNA in a process

  • called RNA splicing.

  • And it's. something. like. editing. this. video.

  • The process is really complicated, but I just had to tell you about two of the key players

  • because they have such cool names.

  • One, the Snurps, which are Small Nuclear RibonucleoProteins.

  • These are a combination of RNA and proteins, and they recognize the sequences that signal

  • the start and end of the areas to be spliced.

  • Snurps bunch together with a bunch of other proteins to form the spliceosome, which is

  • what does the actual editing

  • as it were, breaking the junk segments down so their nitrogenous bases can be reused in

  • DNA or RNA, and sticking together the two ends of the good stuff.

  • The good stuff that gets spliced together, by the way, are called exons because they'll

  • eventually be expressed

  • the junk that gets cut out are just intervening segments, or introns.

  • The material in the introns will stay in the nucleus and get recycled.

  • So for instance, titin down there is thought to have hundreds of exons when it's all said and done

  • probably more than 360, which may be more than any other protein.

  • And it also contains the longest intron in humans, some 17,000 base pairs long.

  • Man, titian! It is just a world record holder!

  • So now that it has been protected and refined, the messenger RNA can now move out of the nucleus.

  • OK, a quick review of our Hot Pocket Mission Impossible caper so far:

  • We broke into the lair containing the instructions, we copied down those instructions in shorthand

  • we added some protective coatings, and then we cut out some extra notes that we didn't need

  • and then we escaped back out of the lair.

  • Now I have to actually read the notes, make the machinery and assemble the ingredients.

  • This process is called translation.

  • So next, rewind your memory -- or just watch that video again -- to the episode about animal cells.

  • Do you remember the rough endoplasmic reticulum? I hope you do.

  • Those little dots on the membranes are the ribosomes, and the processed messenger RNA

  • gets fed into a ribosome like a dollar bill into a vending machine.

  • Ribosomes are a mixture of protein and a second kind of RNA, called ribosomal RNA [rRNA]

  • and they act together as a sort of work space.

  • rRNA doesn't contribute any genetic information to the process, instead it has binding sites

  • that allow the incoming mRNA to interact with another special type of RNA

  • the third in this caper, called transfer RNA, or tRNA.

  • And tRNA really might as well be called 'translation RNA' because that's what it does

  • it translates from the language of nucleotides into the language of amino acids and proteins.

  • On one end of the tRNA is an amino acid. On the other end is a specific sequence of three

  • nitrogenous bases.

  • These two ends are kind of matched to each other.

  • Each of the 20 amino acids that we have in our body has its own sequence at the end.

  • So if the tRNA has the amino acid methionine on one end, for instance, it can have UAC,

  • as the nucleotide sequence on the other.

  • Now it's like building a puzzle. The mRNA slides through the ribosome.

  • The ribosome reads the mRNA three letters at a time - each set called a triplet codon.

  • The ribosome then finds the matching piece of the puzzle: a tRNA with three bases that

  • will pair with the codon sequence.

  • That end of the tRNA, by the way, is called the anticodon.

  • Sorry for all the terminology.

  • YOU NEED TO KNOW IT!

  • And of course, by bringing in the matching tRNA, the ribsome is also bringing in whatever

  • amino acid is on that tRNA.

  • Ok so, starting at the 5' end of the mRNA that's fed into the ribosome, after the

  • 5' cap, for almost every gene, you find the nucleotide sequence AUG on the mRNA.

  • The ribosome finds a tRNA with the anticodon UAC, and on the other end of that tRNA is methionine.

  • The mRNA, like a mile-long dollar bill, keeps sliding into the ribosome so that the next

  • codon can be read, and another tRNA molecule with the right anticodon binds on.

  • If the codon is UUA, the matching tRNA has AAU on one end and Leucine on the other

  • and if the mRNA has AGA, the matching tRNA has UCU on one end and Arginine on the other.

  • In each case that new amino acid gets connected to the previous amino acid - starting a polypeptide chain.

  • Which is the beginning, the very beginning of a protein.

  • But it turns out there are LOTS of different ways to read this code.

  • 'Cause UUA is not the only triplet that codes for Leucine -- UUG does too!

  • And argenine is coded for by six different triplets!

  • This is actually a good thing. It means that we can make a few errors in copying, transcribing

  • and translating DNA, and we won't necessarily change the end product.

  • This process continues, with the mRNA sliding in a bit, the ribosome bringing in a tRNA

  • with an amino acid, that amino acid binding to the existing chain

  • and on and on, sometimes for thousands of amino acids to make a single polypeptide chain,

  • for example.

  • This whole word is basically just the names of the amino acids in the sequence in the

  • order in which they occur in the protein

  • all 34,350 of them.

  • But before we can make our own hot pockets

  • and that string of amino acids becomes my muscle tissue

  • we have some folding to do.

  • That's because proteins, in addition to being hella big, can also contort into very

  • complex and downright lovely formations.

  • One key to understanding how a protein works is to understand how it folds, and scientists

  • have been working for decades on computer programs to try to figure out protein folding.

  • Now, the actual sequence of amino acids in a polypeptide - what you see scrolling along

  • down there - is called its primary structure.

  • One amino acid covalently bonded to another, and that one to another, in a single file.

  • But some amino acids don't like to just hold hands with two others, they're a bit

  • more promiscuous than that.

  • The hydrogens on the main backbone of the amino acids like to sometimes form bonds on

  • the side (hydrogen bonds) to the oxygens on amino acids a few doors down.

  • When they do that, depending on the primary structure, they bend and fold and twist into

  • a chain of spirals, called a helix.

  • We also find several kinked strands laying parallel to one another, called pleated sheets.

  • All those hydrogen bonds in pleated sheets are what make silk strong, for instance.

  • So in the end, our promiscuous amino acids lead to wrinkled sheets. Ah-hah!

  • These hydrogen bonds help give polypeptides their secondary structure.

  • But it doesn't end there. Remember the R groups that define each amino acid?

  • Some of them are hydrophobic. Since the protein is in the cell, which is mostly water, all

  • those hydrophobic groups try to hide from the water by huddling together, and that can

  • bend up the chain some more.

  • Other R groups are hydrophilic, which if nothing else means that they like to form hydrogen

  • bonds with other hydrophilic R groups.

  • So we get more bonding, and more bending, and our single-file line has now taken on

  • a massively complex 3-D shape.

  • It also explains why I can fix my bed-head by wetting my hair with water.

  • The water helps break some of those hydrogen bonds in the keratin which relaxes its structure.

  • That way I can comb it out, and when it dries those bonds reform and voila, perfect hair.

  • All of this shape caused by bonding between R groups gives our polypeptide a tertiary structure.

  • So now we have a massively contorted polypeptide chain, and it actually contorts very precisely.

  • Sometimes, just one chain is what makes up the whole enzyme or protein.

  • In other proteins, like hemoglobin, several different chains come together to from a quaternary structure.

  • So a quick review of structure: the sequence is primary, the backbone hydrogen bonds forming

  • sheets and spirals are secondary, R group bonds are tertiary, and the arrangement of

  • multiple proteins together give quaternary structure.

  • These polypeptides are either structural proteins, like this thing at the bottom here that you

  • can find in muscle or in my hot pocket.

  • They might also be enzymes, and enzymes like, do stuff.

  • They can cut up biological molecules like I do with this chef's knife, they can mix

  • stuff and they can put stuff together.

  • So from that one recipe book we got all of the ingredients and all of the tools necessary

  • to make me, which is better than a hot pocket.

  • Would you all agree?

  • Now take your time with this stuff, feel free to watch the episode a couple of times, because

  • next week we're going to talk about how cells swap all of this

  • genetic information through reproduction.

  • Thank you for watching this episode.

  • By now, you should probably know how this works.

  • You can click on any of the links over there, and it'll take you back to that point in the

  • show as long as you are not watching on your cell phone.

  • It doesn't work on cell phones, I apologize for that.

  • Thank you to everyone who helped us put this show together, and thank you to you, for watching it today.

  • If you have any questions about this episode please leave them in the comments below, or

  • you can get us on Facebook or Twitter.

  • And that's all. Goodbye!

Ok, roll it.

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