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[Music]

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so hello everyone my name is Nicolas

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Kovich my advisor is dr. Lauren Williams

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and we are at the Georgia Tech at

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Georgia Tech in Atlanta Georgia on the

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bioinformatics PhD candidate the school

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of chemistry and biochemistry and my

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talk today is titled frozen in time the

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history of proteins so I'll be talking

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about a really large molecular structure

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but I swear it pertains to the origin of

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life so just bear with the introduction

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I'll get to it eventually um so just a

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brief introduction about the central

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dogma of molecular biology I'm sure all

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of you guys are familiar with this but

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just to touch base with it for some of

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those geologists or some other people so

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here on the Left we have DNA and it's a

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nucleic acid polymer and on it

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we have encoded genes amongst other

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things but genes where we can talk about

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and over here in the blue we have an

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enzyme RNA polymerase which reads the

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DNA and looks at just the genes and

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copies those into RNA

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another nucleic acid polymer and so it's

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RNA then just has just the one gene on

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it and this gene on the mRNA goes to the

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ribosome and the ribosome then reads the

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mRNA it makes a protein and amino acid

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polymer and so I will be talking about

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the ribosome right here the key in it

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which reads RNA and makes protein so

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looking at the ribosome it has two

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subunits the small subunit and the large

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subunit the log the small subunit is all

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left and the large subunit is on the

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right RNA I have colored in pink and

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yellow and in blue are ribosomal

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proteins and then right there in the

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green at the very center of the large

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subunit is where peptide bond catalysis

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happens that is called the petiole

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transferase center and this particular

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transferase center is exclusively RNA so

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the ribosome is a ripe design

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okay so like I said the ribosome reads

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RNA it makes protein or it reads nucleic

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acid polymers and it makes an amino acid

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polymer or another way of saying that is

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its input as information and its output

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is a function so in 2009 the Nobel Prize

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in Chemistry was awarded to thanking

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ramakrishnan commerce sites in a tea

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oneth for the studies of the structure

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and function of the ribosome and they

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made this really cool animation and it's

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very complex but is this is the

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introduction of the ribosome so I just

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want to show you that on the bottom here

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we have the small subunit that's in

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transparent pink on the top we have and

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this transparent yellow that would be

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the large subunit the mRNA is in blue

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and it's being read by the small subunit

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and these structures going in and out of

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here are T RNAs and they're bringing

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amino acids and these amino acids are

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brought to the peptidyl transferase

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center right in the middle of the large

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subunit and they get strung together to

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make a peptide that then emerges out the

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back of the ribosome so now to look at

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the sequence of the ribosome so I'm sure

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many of you are familiar with

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phylogenetic trees of life where we have

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the three domains of life bacteria

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archaea and Eukarya over here we have

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animals and their distant relates a

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fungi and plants then we have our cans

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which are then you can barley distantly

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related to eukaryotes and then bacteria

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are all over here

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and so these phylogenetic trees are made

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by looking at the sequence of ribosomal

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genes so the ribosomal RNA and ribosomal

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proteins are encoded on the genome of

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all of every organism and so just the

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ribosomal RNA genes are just not made

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into protein they just stay as RNA but

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we can just be looking at the sequence

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and that's how we construct these

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phylogenetic trees so the ribosome has

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within it like the interrelatedness of

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all of life so looking at the ribosome

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from across the Tree of Life we can see

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that bacteria the large subunit has two

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ribosomal RNAs and

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33 ribosomal proteins where it's a small

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subunit has one ribosomal RNA and 22

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ribosomal proteins are kaons then have a

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few more ribosomal proteins and both

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both its large subunit and small subunit

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and then eukaryotes have one more one or

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two more ribosomal RNAs in its large

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subunit and a few more ribosomal

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proteins in both its l-s-u large living

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it and SS you small so you

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and so bacterias ribosomes are pretty

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small whereas our cans are a little bit

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bigger and eukaryotes have very large

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ribosomes so to conclude this

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introduction on the ribosome its

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sequence and structure ribosomes are

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made of both RNA and protein ribosomal

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RNA and protein sequences describe the

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interrelatedness of life and ribosomes

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size is highly correlated with species

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complexity

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here's another phylogenetic tree so on

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the top we have homo sapiens and below

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that shrimps so those are mammals and

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then farther down we have chicken and

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[Music]

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let's see mosquito right there so those

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are animals and then further down here

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we have single-celled eukaryotes like

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ester Vissi a fungus and what else we

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have here

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I think Plasmodium falciparum which is

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the parasite that causes malaria and

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then down here I just have archaea and

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bacteria because what I'm trying to show

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in this phylogenetic tree is the size of

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the ribosome so bacteria the ribosome is

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all about the same size but the sequence

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is very different and the same with our

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kaons their ribosomes a little bit

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larger than bacteria but their sequence

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is very different within the whole

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entire domain whereas eukaryotes there's

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like a really big difference in their

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size of the ribosomes and so that's what

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I have over here and these circles so

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bacteria the ribosome is small and

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Arcadians is also fairly small then the

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single cellular eukaryotes have you know

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medium sized ribosomes these animals

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have even larger ribosomes

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then mammals have the largest ribosomes

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that we see this so this is very highly

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correlated to how complex a species

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species is people used to think oh well

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maybe like the length

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you know the DNA of an organ organism

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would tell you how complex that species

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is but there is some really big

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anomalies that really just throw it off

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for instance the marble bunk fish has

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its genome was 120 billion nucleotides

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long

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whereas humans it's 6 billion so really

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that's not like a really good indication

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of how complex this species is okay so

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what am i doing in my project so I'm

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looking at the ribosome and I'm

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constructing a data set of its structure

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and the reason I'm doing that is because

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the ribosome is the origin of life it

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contains within its structuring sequence

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the history of protein folding and I

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believe that by mining the structure of

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it and the sequence set I can unravel

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how life has evolved so like I said I'm

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looking at structures of ribosomes and

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in 2009 the Nobel Prize was awarded for

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the structure for crystallize in

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ribosome and since then we have quite a

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few structures so we have bacteria E

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coli and thermus thermophilus on the

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Left we have the large subunit and on

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the right we have the small subunit we

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have the Arcadians halo rocky lamar

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smart i and pirate caucus furiosa s'

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halo arkla we only have a large subunit

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not the small subunit we can get

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crystallized we also have the protozoan

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a single cellular eukaryote again we

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only have the large subunit we have the

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single cellular fungi Saccharomyces

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cerevisiae the animals Drosophila like

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gaster and Homo sapiens fruit fly in

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humans and we also have the human

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protozoan parasites that cause malaria

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and African sleeping sickness and so

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what happens when we align all these on

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to each other well as you can see

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bacteria and archaea have pretty small

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ribosomes but then when you start

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putting on eukaryotes it gets a little

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bigger and larger and larger and then I

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have these human protozoan parasites

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over here for a discussion later on that

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maybe you have but for the focus of this

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talk I'm not going to talk too much

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about them but as you can see these

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structures are quite a bit larger than

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the E coli and other bacterial species

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and when we get is we get this big glob

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of like hundreds of millions of atoms

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and we really can't make sense of it

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when you look at that but when you look

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deep within its structure you can see

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that the structures of the RNA and the

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protein that make up the ribosome and

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the center of it are miraculously just

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similar their sequence is different but

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their structure is just crazy the same

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going from the center all the way out to

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near the surface of it it's only the

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surface of the ribosomal ribosomal

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structures that we see any variation so

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the center of it is just a common core

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of structure that just doesn't divulge

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from any species that we know of and

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it's when we look at the surface then

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so looking at that one helix from the

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last slide this is helix 25 and I'll

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just use this as an example to show you

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how ripe Izumo

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RNA has evolved so this helix 25 of

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bacteria we have our k ends protozoans

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fungi animals and our parasitic

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protozoan x' and then when we align

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these onto each other and this is

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aligning the ribosomes I'm just I'm just

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cutting away the rest of the ribosome

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and only looking at this helix that's on

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the surface we can see that the

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structure is also very conserved at that

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very first helix but there's HeLa C's

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budding off of that and as you can see

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going through more and more complex

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species you can see that this helix is

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just has more and more HeLa C's just

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budding off of it and so we believe that

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this is how the ribosome has a ribosome

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while RNA has evolved is that just HeLa

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sees just butted off from other HeLa C's

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and so this kind of so to wrap that up

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the ribosome has a common core and it's

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made of RNA and protein and the RNA is

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really conserved in structure but not

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sequence and these sites of ribosomal

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RNA evolution are referred to as

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expansion segments and they but offer

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the common core of the ribosome and they

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do not perturb the common core structure

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and the sounds to make an analogy

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it's kind of like a tree when you look

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at a tree you can tell the newest

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sections of it are the leaves whereas

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the oldest section is the trunk and so

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we're looking at these structures and

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we're seeing these eukaryotic expansion

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segments those are like the leaves and

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the outermost branches and when we take

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away these leaves and take away these

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branches we can just go deeper and

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deeper into the past the ribosome and we

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eventually get to just one helix and

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that would just be the trunk of the tree

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this one helix is the peptidyl

275
00:11:43,470 --> 00:11:40,839
transferase center so it's where peptide

276
00:11:48,389 --> 00:11:43,480
bonds are made and so we can look at how

277
00:11:50,609 --> 00:11:48,399
the ribosomal RNA has evolved okay so

278
00:11:52,559 --> 00:11:50,619
that's the RNA of the ribosome well what

279
00:11:55,199 --> 00:11:52,569
about the protein well the protein is

280
00:11:57,749 --> 00:11:55,209
also very similar in some regards so

281
00:12:01,859 --> 00:11:57,759
this is universal protein number four of

282
00:12:04,429 --> 00:12:01,869
the large subunit ul4 and so for those

283
00:12:07,229 --> 00:12:04,439
of you who are familiar with proteins or

284
00:12:09,150 --> 00:12:07,239
maybe not I guess up here we have a

285
00:12:11,069 --> 00:12:09,160
globular domain and that looks a lot

286
00:12:13,229 --> 00:12:11,079
like the proteins we see in all white

287
00:12:14,939 --> 00:12:13,239
today but these ribosomal proteins are

288
00:12:17,129 --> 00:12:14,949
very weird looking they have these

289
00:12:18,989 --> 00:12:17,139
really strange like tails that just go

290
00:12:20,489 --> 00:12:18,999
into the ribosome and they don't really

291
00:12:23,309 --> 00:12:20,499
look like other proteins that we know

292
00:12:24,509 --> 00:12:23,319
and so a lot of people just don't really

293
00:12:26,159 --> 00:12:24,519
look at them and they throw them out of

294
00:12:27,329 --> 00:12:26,169
their analysis and stuff like that but

295
00:12:30,689 --> 00:12:27,339
I'm looking at them because I think

296
00:12:33,329 --> 00:12:30,699
they're interesting and so this is ul4

297
00:12:35,039 --> 00:12:33,339
from a bacterial species and that's uo4

298
00:12:38,189 --> 00:12:35,049
from an our canyon and that's you all

299
00:12:40,079 --> 00:12:38,199
for from eukaryote and then when we look

300
00:12:42,840 --> 00:12:40,089
at them within these aligned crystal

301
00:12:47,129 --> 00:12:42,850
structures we see that they line right

302
00:12:49,739 --> 00:12:47,139
on top of each other and they all have

303
00:12:51,569 --> 00:12:49,749
this tail that goes deep into the

304
00:12:53,789 --> 00:12:51,579
ribosome and they have this globular

305
00:12:56,309 --> 00:12:53,799
domain that hasn't really changed in

306
00:12:57,929 --> 00:12:56,319
structure either but then arcane's and

307
00:13:00,239 --> 00:12:57,939
eukaryotes have this little loop here

308
00:13:01,919 --> 00:13:00,249
and then eukaryotes have a little bit

309
00:13:04,559 --> 00:13:01,929
more over here and there's large alpha

310
00:13:07,049 --> 00:13:04,569
helix that buds off there and this goes

311
00:13:09,539 --> 00:13:07,059
on to the surface of the ribosome where

312
00:13:12,269 --> 00:13:09,549
the ribosome has been evolving but all

313
00:13:14,879 --> 00:13:12,279
has this common core right here and this

314
00:13:17,340 --> 00:13:14,889
common core goes deep into the ribosome

315
00:13:18,790 --> 00:13:17,350
and it goes right next to the peptidyl

316
00:13:22,569 --> 00:13:18,800
transferase center

317
00:13:24,369 --> 00:13:22,579
right here and so it's almost like if

318
00:13:27,609 --> 00:13:24,379
you are looking make a reaction

319
00:13:29,829 --> 00:13:27,619
coordinate of this that you know here

320
00:13:32,019 --> 00:13:29,839
would be like the oldest peptides and

321
00:13:34,960 --> 00:13:32,029
here would be the newer ones like I

322
00:13:37,210 --> 00:13:34,970
showed in that last figure the very

323
00:13:39,970 --> 00:13:37,220
center of the ribosome is the oldest

324
00:13:41,859 --> 00:13:39,980
part it's the oldest ribosomal RNA

325
00:13:44,470 --> 00:13:41,869
whereas the outside is the newest and

326
00:13:48,069 --> 00:13:44,480
when you look at these proteins it's the

327
00:13:50,109 --> 00:13:48,079
same the proteins that protein the amino

328
00:13:52,269 --> 00:13:50,119
acids and peptides are closest to the

329
00:13:54,489 --> 00:13:52,279
petiole transfer a center or the oldest

330
00:13:57,309 --> 00:13:54,499
ones where the ones on the exterior of

331
00:13:59,859 --> 00:13:57,319
the ribosome are the newest ones and so

332
00:14:04,600 --> 00:13:59,869
looking at this we can see how proteins

333
00:14:06,910 --> 00:14:04,610
have evolved since the origin of life so

334
00:14:10,119 --> 00:14:06,920
I made this like protein folding peak

335
00:14:14,530 --> 00:14:10,129
and so basically what it was showing is

336
00:14:15,939 --> 00:14:14,540
that close to the center of the peptidyl

337
00:14:18,609 --> 00:14:15,949
transferase center we get these

338
00:14:20,319 --> 00:14:18,619
unstructured peptides but then as you

339
00:14:22,030 --> 00:14:20,329
move farther and farther out from it you

340
00:14:24,699 --> 00:14:22,040
start saying okay well there's like some

341
00:14:27,160 --> 00:14:24,709
you know beta sheets or beta hairpins

342
00:14:29,230 --> 00:14:27,170
and then you move farther out then you

343
00:14:30,819 --> 00:14:29,240
start seeing like beta barrels and as

344
00:14:32,699 --> 00:14:30,829
you go into the surface of the ribosome

345
00:14:35,980 --> 00:14:32,709
then you see is really complex looking

346
00:14:39,549 --> 00:14:35,990
proteins that we see in all of cellular

347
00:14:41,379 --> 00:14:39,559
life and so it it's a reaction

348
00:14:43,929 --> 00:14:41,389
coordinate of how proteins have evolved

349
00:14:46,509 --> 00:14:43,939
since the origin of life and so that's

350
00:14:47,859 --> 00:14:46,519
what I have been looking at and so to

351
00:14:50,710 --> 00:14:47,869
conclude these ribosomal protein

352
00:14:53,289 --> 00:14:50,720
evolution you can see that ribosomal

353
00:14:54,910 --> 00:14:53,299
proteins have also have expansions and

354
00:14:57,519 --> 00:14:54,920
this is very similar to the ribosomal

355
00:14:59,109 --> 00:14:57,529
RNA however these ribosomal protein

356
00:15:00,970 --> 00:14:59,119
structural differences are much more

357
00:15:02,559 --> 00:15:00,980
pronounced we just know a lot more about

358
00:15:04,749 --> 00:15:02,569
proteins proteins have been struck

359
00:15:06,639 --> 00:15:04,759
studied for a while whereas RNA the

360
00:15:08,319 --> 00:15:06,649
structures and everything haven't been

361
00:15:11,199 --> 00:15:08,329
very interesting to a lot of people for

362
00:15:13,359 --> 00:15:11,209
much time and these that these ribosomal

363
00:15:16,269 --> 00:15:13,369
proteins there's a common core to it and

364
00:15:18,850 --> 00:15:16,279
the common core just like RNA no protein

365
00:15:20,530 --> 00:15:18,860
is all exactly the same the sequence

366
00:15:23,650 --> 00:15:20,540
might differ but the structure is the

367
00:15:25,569 --> 00:15:23,660
same and so we believe that ribosomal

368
00:15:28,030 --> 00:15:25,579
evolution happens in both RNA and

369
00:15:29,769 --> 00:15:28,040
protein and the RNA and protein have

370
00:15:30,810 --> 00:15:29,779
evolved together in a mutualistic

371
00:15:34,530 --> 00:15:30,820
fashion

372
00:15:36,390 --> 00:15:34,540
and then so to conclude I just like to

373
00:15:38,480 --> 00:15:36,400
do show this one slide from a project

374
00:15:41,160 --> 00:15:38,490
I'm working on because we're all

375
00:15:42,540 --> 00:15:41,170
astrobiologists here and it's a little

376
00:15:44,340 --> 00:15:42,550
bit talking about metals and I just

377
00:15:46,560 --> 00:15:44,350
maybe want to show some people so that

378
00:15:51,090 --> 00:15:46,570
maybe they can give me some input later

379
00:15:53,610 --> 00:15:51,100
on so a lot of these ribosomal proteins

380
00:15:55,560 --> 00:15:53,620
are binding zinc and zinc is very

381
00:15:57,660 --> 00:15:55,570
important for a lot of proteins in

382
00:16:00,570 --> 00:15:57,670
looking at any organism that we see

383
00:16:03,320 --> 00:16:00,580
around today you know four to 10% of

384
00:16:05,400 --> 00:16:03,330
their proteins need zinc to function and

385
00:16:07,650 --> 00:16:05,410
zinc is found in many of these ribosomal

386
00:16:09,420 --> 00:16:07,660
proteins and these proteins that it's in

387
00:16:12,150 --> 00:16:09,430
are usually very simple-looking

388
00:16:13,500 --> 00:16:12,160
so here's one of them and so there's the

389
00:16:16,250 --> 00:16:13,510
zinc that's coordinating with four

390
00:16:19,560 --> 00:16:16,260
cystines and it's just made of like to

391
00:16:23,160 --> 00:16:19,570
beta hairpins and so and I'm looking at

392
00:16:24,690 --> 00:16:23,170
this it's like it's pretty these

393
00:16:27,360 --> 00:16:24,700
proteins are usually found pretty deep

394
00:16:28,760 --> 00:16:27,370
within the ribosome and I believe that

395
00:16:33,180 --> 00:16:28,770
these could be some very ancient

396
00:16:35,160 --> 00:16:33,190
peptides or proteins and I'm looking at

397
00:16:37,350 --> 00:16:35,170
the literature and you know there's all

398
00:16:39,240 --> 00:16:37,360
sorts of you know hypothesis of how like

399
00:16:41,460 --> 00:16:39,250
the world came about and everything and

400
00:16:43,110 --> 00:16:41,470
what kind of concentrations models were

401
00:16:45,600 --> 00:16:43,120
at and everything and you know there's

402
00:16:48,290 --> 00:16:45,610
some debate about zinc and whatnot but

403
00:16:50,760 --> 00:16:48,300
our lab has also shown in the past that

404
00:16:53,010 --> 00:16:50,770
you know the ribosome needs magnesium

405
00:16:55,200 --> 00:16:53,020
cations to stabilize its tertiary

406
00:16:58,290 --> 00:16:55,210
interactions between the RNA HeLa C's

407
00:16:59,640 --> 00:16:58,300
because they're very negative and there

408
00:17:02,760 --> 00:16:59,650
have been studies in our lab and other

409
00:17:04,800 --> 00:17:02,770
labs that have shown that you know RNA

410
00:17:08,430 --> 00:17:04,810
doesn't necessarily need magnesium but

411
00:17:10,200 --> 00:17:08,440
it could be using reduced iron and I

412
00:17:13,410 --> 00:17:10,210
found some literature saying that these

413
00:17:15,570 --> 00:17:13,420
peptides these zinc ribbons that these

414
00:17:20,400 --> 00:17:15,580
original proteins have that they can

415
00:17:21,870 --> 00:17:20,410
also bind iron instead of zinc and so

416
00:17:24,300 --> 00:17:21,880
hopefully tomorrow I can like look at

417
00:17:26,070 --> 00:17:24,310
some posters and maybe some talks and

418
00:17:29,160 --> 00:17:26,080
hopefully some we talking about zinc or

419
00:17:30,630 --> 00:17:29,170
iron or something like that but so I

420
00:17:32,430 --> 00:17:30,640
guess that will be conclude it um

421
00:17:35,220 --> 00:17:32,440
there's really not much to put in this

422
00:17:43,230 --> 00:17:35,230
presentation summary but this is our lab

423
00:17:50,430 --> 00:17:45,700
all right we got time for one quick

424
00:17:57,970 --> 00:17:53,770
um yeah I'm so my question if you can go

425
00:18:02,890 --> 00:17:57,980
back to slides sorry uh what are the

426
00:18:05,020 --> 00:18:02,900
arrows on the protein fold okay so it's

427
00:18:09,100 --> 00:18:05,030
just showing like so I go the way you

428
00:18:11,140 --> 00:18:09,110
like depict the protein is these arrows

429
00:18:12,880 --> 00:18:11,150
are just beta sheets and so that's just

430
00:18:15,760 --> 00:18:12,890
how it's like structured and so right

431
00:18:18,340 --> 00:18:15,770
between that like this is a simplistic

432
00:18:20,320 --> 00:18:18,350
diagram you have your amino acids and

433
00:18:22,420 --> 00:18:20,330
they're aligning and hydrogen bonding to

434
00:18:24,720 --> 00:18:22,430
each other and then the arrow is just

435
00:18:26,620 --> 00:18:24,730
pointing to like okay so this is the

436
00:18:30,370 --> 00:18:26,630
n-terminal and then this is the

437
00:18:31,810 --> 00:18:30,380
c-terminus of the protein so it's just a

438
00:18:35,320 --> 00:18:31,820
simple way of drawing a protein

439
00:18:35,860 --> 00:18:35,330
structure mm-hmm alright thank you very

440
00:18:37,180 --> 00:18:35,870
much

441
00:18:38,900 --> 00:18:37,190
Thanks