P53, the super protein

P53 the super protein

Inevitably when taking any biochem class you going to encounter some cool proteins. There are proteins that look cool, proteins with cool sub-groups and proteins that have some cool chemistry involved. None of theses are even close to the awesome protein that is P53. Now I know what you are thinking, with a name so bland as P53 this protein has to suck. You couldn't be more wrong. P53 goes by many names "Tumor Suppressor Protein", "Guardian of the Genome", and "The Coolest Protein Ever". Are these names warranted? Absolutely.

STRUCTURE

In order to fully appreciate you need to start with the structure. P53 is flexible protein, so instead of all of those boring enzymes with fixed structures, P53 has a continually changing structure. That's right, it's too cool for X-ray crystallography. The best that scientists can do is determine a few rigid domains in the overall structure. First off, in the middle, is the tetramerization domain. If you thought one subunit could control this protein you were wrong. Second is the DNA binding domain. This is the part of the protein that binds directly to the most important molecule in your body, your DNA. Lastly is the transactivation domain, this domain helps the protein read your DNA. All together these three domains work in perfect unison creating the most amazing protein that your body has to offer.

FUNCTION

P53 is the most researched protein you will ever see. Why is this? It is because P53 stops cancer. That's right boys and girls, this protein stops cancer, how could you vote for anything else. If that wasn't enough lets go more in depth on exactly how it works. P53 is made just like any other protein. It is made by mRNA in the ribosome creating proteins. The difference between P53 and any other normal protein is that P53 turns right back around to the DNA whence it came, and starts telling it where it went wrong. P53 is literally too cool for DNA. When a cell's DNA is damaged the DNA looks different. It is usually too wide because there is an extra nucleic acid or because the nucleic acids don't base pair and cause a bulge. This DNA damage is then detected and P53 is phosphorylated.  So what happens when P53 sees some damaged DNA? It casually sends some signals, and stops the entire cell cycle. When P53 says stop the entire cell listens. But it just keeps getting cooler. It then tries to repair the DNA. Just for a little review you need to remember that DNA is what makes other proteins. P53 is the super protein that makes sure all the other proteins are in line, it's that big of a deal. But what happens if the DNA can't be repaired? Good question. P53 then sends signals for the cell to kill itself, and the cell does. P53 has the ability to kill the entire cell if it isn't happy. It's just that badass. 

REGULATION

Now before you go on thinking that P53 is regulated by some mere hormone or simple phosphorylation like other inferior proteins, you need to think. Would P53 really succumb to regulation that easily? Of course not, introducing MDM2. This isn't a hormone but an entire protein whose only job is to hold P53 back. When MDM2 is bound to P53 activity is lowered. In fact without MDM2 cells are unable to live because P53 is just too awesome to exist without regulation. MDM2 binds to and blocks the transactivation region of P53. MDM2 also acts as an E3 ubiquitin ligase. When ubiquitin is bound to P53, it will be transported out of the nucleus and eventually degraded. They need to catch P53 out of it's environment before they dare to take it down, that's hardcore. So together MDM2 and P53 for a dynamic cancer fighting super duo that keeps your cells in check and out of trouble. Remember don't vote for any of the other boring proteins you see. Vote for the protein with the ability to kill an entire cell just because it's unhappy.  

Typical MDM2, having to gang up on P53 just to keep it down.

Images:
-http://www.rcsb.org/pdb/101/motm.do?momID=31&evtc=Suggest&evta=Moleculeof%20the%20Month&evtl=TopBar
-http://upload.wikimedia.org/wikipedia/commons/9/9a/P53_pathways.jpg

-http://www.nature.com/ncb/journal/v9/n4/images/ncb1562-f5.jpg

P53 the super protein

Inevitably when taking any biochem class you going to encounter some cool proteins. There are proteins that look cool, proteins with cool sub-groups and proteins that have some cool chemistry involved. None of theses are even close to the awesome protein that is P53. Now I know what you are thinking, with a name so bland as P53 this protein has to suck. You couldn't be more wrong. P53 goes by many names "Tumor Suppressor Protein", "Guardian of the Genome", and "The Coolest Protein Ever". Are these names warranted? Absolutely.

STRUCTURE

In order to fully appreciate you need to start with the structure. P53 is flexible protein, so instead of all of those boring enzymes with fixed structures, P53 has a continually changing structure. That's right, it's too cool for X-ray crystallography. The best that scientists can do is determine a few rigid domains in the overall structure. First off, in the middle, is the tetramerization domain. If you thought one subunit could control this protein you were wrong. Second is the DNA binding domain. This is the part of the protein that binds directly to the most important molecule in your body, your DNA. Lastly is the transactivation domain, this domain helps the protein read your DNA. All together these three domains work in perfect unison creating the most amazing protein that your body has to offer.

FUNCTION

P53 is the most researched protein you will ever see. Why is this? It is because P53 stops cancer. That's right boys and girls, this protein stops cancer, how could you vote for anything else. If that wasn't enough lets go more in depth on exactly how it works. P53 is made just like any other protein. It is made by mRNA in the ribosome creating proteins. The difference between P53 and any other normal protein is that P53 turns right back around to the DNA whence it came, and starts telling it where it went wrong. P53 is literally too cool for DNA. So what happens when P53 sees some damaged DNA? It casually sends some signals, and stops the entire cell cycle. When P53 says stop the entire cell listens. But it just keeps getting cooler. It then tries to repair the DNA. Just for a little review you need to remember that DNA is what makes other proteins. P53 is the super protein that makes sure all the other proteins are in line, it's that big of a deal. But what happens if the DNA can't be repaired? Good question. P53 then sends signals for the cell to kill itself, and the cell does. P53 has the ability to kill the entire cell if it isn't happy. It's just that badass. 

REGULATION

Now before you go on thinking that P53 is regulated by some mere hormone or simple phosphorylation like other inferior proteins, you need to think. Would P53 really succumb to regulation that easily? Of course not, introducing MDM2. This isn't a hormone but an entire protein whose only job is to hold P53 back. When MDM2 is bound to P53 activity is lowered. In fact without MDM2 cells are unable to live because P53 is just too awesome to exist without regulation. So together MDM2 and P53 for a dynamic cancer fighting super duo that keeps your cells in check and out of trouble. Remember don't vote for any of the other boring proteins you see. Vote for the protein with the ability to kill an entire cell just because it's unhappy.  

Images:

-http://www.rcsb.org/pdb/101/motm.do?momID=31&evtc=Suggest&evta=Moleculeof%20the%20Month&evtl=TopBar

-http://upload.wikimedia.org/wikipedia/commons/9/9a/P53_pathways.jpg

P-53 in papers

P53 is kind of a big deal in the literature and it is hard to pick just one paper to look at but here are 3 that focus on P53's function and chemistry



http://www.cbi.pku.edu.cn/chinese/documents/cell/xibaoshengwuxuecankaowenxian/cocb/13/13-3/13(3)-12.pdf

      This review paper focuses mainly on regulation and function of P53. As most people know P53 is the cancer protein, It's main function is to repair damaged cell DNA. It does this by first stoping cell cycle and then either repairing the damaged DNA or causing apoptosis. Once P53 detects DNA damage it acts as a transcription factor activating other proteins. It has a multifaceted response though and the exact mechanism that it uses to trigger apoptosis is not entirely known.

There are numerous regulators of P53 the main enzyme that this paper talks about is MDM2(Mouse double minute 2 homolog). MDM2 both acts as an inhibitor for P53 and a agent for degradation. P53 must be in the nucleus in order to have an effect. MDM2 will ubiqunate both itself and P53 targeting it for nuclear export and degradation. 

http://genesdev.cshlp.org/content/12/18/2831.full.pdf+html

This is a primary research paper that talks about the mechanism for P53 activation.  Cell damage leads to both acetylation and phosphorylation of P53. Two different histone acetyltransferases, theses acetylate lys residues in the carboxyl terminus of P53. This in turn adds to P53's DNA affinity and it's activity as a transcription factor. The paper also mentions the phosphorylation of two serine residues in activating P53.

http://www.nature.com/onc/journal/v24/n17/full/1208615a.html

The last review paper talks about the complexity of P53 and the pathways that it influences. Because cell replication is such a complicated process P53 has to effect many different proteins in order to do it's job. This paper metions over ten feedback loops that P53 is directly involved in. Six of these are directly involved with MDM2, P53s main regulatory protien but there are many more. Some listed are Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin G-PP2A, and p73 gene product. The figure below should give you an idea of just how many different cycles P53 is involved in.

molecule of the month link: http://www.rcsb.org/pdb/101/motm.do?momID=31&evtc=Suggest&evta=Moleculeof%20the%20Month&evtl=TopBar

Protein Pictures

Protein Code: 1tup

My protein is P53 or the tumor suppresser protein. From what I understand it is kind of a big deal and hopefully I will be able to find out why. 

 The first picture is simply a Picture using cartoons and a different color for each of the different chains. The DNA looking thing is green is DNA. The Protein looking chains are chains of the protein.

 This is a surface area model showing just how close the bonding is between the the DNA(green) and the protein(red). It looks like they are more than just friends.

 In this beautiful picture I tried to show what it would be like looking down the DNA(white). The protein color makes it a little harder to see the chains, because they're rainbow colored.  They are rainbow colored because it was an option, and I couldn't not click it.

 This is a model showing just the protein by the color of it's elements. Carbon is grey, Oxygen is red, Nitrogen is blue, and Sulfur is Orange. It could actually all be grey, I don't know, I'm colorblind.

And Lastly we have a sphere model showing a more toddler friendly version of the protein with no sharp edges.