Do proteins fold differently when folded by different cells?
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Cory J. Geesaman
Oct 1, 2017, 12:52:31 AM10/1/17
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Not necessarily different cells within a single organism, but say you were to splice a really large protein from a Human into a bacteria or the other way around (or any animal or plant or fungus, etc) - when the cell goes to synthesize that protein would it be likely to fold differently? "Likely" meaning "will it fold differently within that cell type more often than it might misfold otherwise."
If there is a difference in the way proteins are folded between different types of cells, is there any relatively comprehensive list of the differences and members of different groups of protein folding/misfolding mechanics?
Skyler Gordon
Oct 1, 2017, 1:17:25 AM10/1/17
to DIYbio
Think about this: based on the contents of different solutions, more/less salt or higher/lower pH, proteins will be either folded (referred to as the proper conformational shape or conformation) or unfolded / denatured. This is because while proteins fold due to internal molecular interactions like hydrogen bonds, a large portion of protein folding has to do with the hydrophobic nature of different amino groups. As the solution changes, so do the hydration shells around the polypeptides and each cell is going to have its own unique internal chemistry.
When it comes to your question it's important to remember that it isn't as simple as just inserting DNA to a cell to get the protein created. Polypeptide chains are often processed through the endoplasmic reticulum, or the Golgi, where they pick up and lose things like disulfide bonds, cell pathway signals, or just help folding to find stable hydrogen bonds.
Protein signaling is pretty complex stuff, and studying the processing of proteins is difficult work. But, it's important to remember that bacteria have been making all the medical insulin on the planet since before either of us was born - so it can be done.
-SG
When it comes to your question it's important to remember that it isn't as simple as just inserting DNA to a cell to get the protein created. Polypeptide chains are often processed through the endoplasmic reticulum, or the Golgi, where they pick up and lose things like disulfide bonds, cell pathway signals, or just help folding to find stable hydrogen bonds.
Protein signaling is pretty complex stuff, and studying the processing of proteins is difficult work. But, it's important to remember that bacteria have been making all the medical insulin on the planet since before either of us was born - so it can be done.
-SG
On Sat, Sep 30, 2017 at 9:52 PM Cory J. Geesaman <co...@geesaman.com> wrote:
Not necessarily different cells within a single organism, but say you were to splice a really large protein from a Human into a bacteria or the other way around (or any animal or plant or fungus, etc) - when the cell goes to synthesize that protein would it be likely to fold differently? "Likely" meaning "will it fold differently within that cell type more often than it might misfold otherwise."If there is a difference in the way proteins are folded between different types of cells, is there any relatively comprehensive list of the differences and members of different groups of protein folding/misfolding mechanics?
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Nathan McCorkle
Oct 1, 2017, 6:59:50 PM10/1/17
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On Sat, Sep 30, 2017 at 9:52 PM, Cory J. Geesaman <co...@geesaman.com> wrote:
> Not necessarily different cells within a single organism, but say you were
> to splice a really large protein from a Human into a bacteria or the other
> way around (or any animal or plant or fungus, etc)
short answer: yes
> Not necessarily different cells within a single organism, but say you were
> to splice a really large protein from a Human into a bacteria or the other
> way around (or any animal or plant or fungus, etc)
look up glycosylation to start
Ravasz
Oct 2, 2017, 5:15:22 AM10/2/17
to DIYbio
I think the correct answer is: "it depends"
For some proteins, you can express them in bacteria or human cells and they will fold in the same manner. But other proteins will fold differently depending on what cell they are expressed in.
This can be due to a number of things. For example some proteins need to be folded into the correct shape by other proteins. Proteins that help other proteins fold correctly are called chaperones. If the chaperone is present in the human cell culture but not in bacteria, then your particular protein will only fold correctly in human cells.
Another reason is post-translational modification, as others have mentioned. After the amino acid chain of a protein is synthesized most proteins will receive phosphorylation, glycosylation, acetylation, methylation, myristoilation and loads of other marks. These modifications will often affect the structure of the protein. Bacteria have a very different system of post-translational modification than human cells, glycosylation being a prime example as stated earlier.
Some proteins require co-factors. These are non-protein molecules that are incorporated into the protein structure. For example, metalloproteases need a certain metal ion to fold correctly. If that particular metal ion is not readily available in the cell you are using, your protein will not fold correctly.
And there are also proteins that should fold in the same manner in both bacteria and human cells but they just don't to annoy you. I hate those proteins.
For some proteins, you can express them in bacteria or human cells and they will fold in the same manner. But other proteins will fold differently depending on what cell they are expressed in.
This can be due to a number of things. For example some proteins need to be folded into the correct shape by other proteins. Proteins that help other proteins fold correctly are called chaperones. If the chaperone is present in the human cell culture but not in bacteria, then your particular protein will only fold correctly in human cells.
Another reason is post-translational modification, as others have mentioned. After the amino acid chain of a protein is synthesized most proteins will receive phosphorylation, glycosylation, acetylation, methylation, myristoilation and loads of other marks. These modifications will often affect the structure of the protein. Bacteria have a very different system of post-translational modification than human cells, glycosylation being a prime example as stated earlier.
Some proteins require co-factors. These are non-protein molecules that are incorporated into the protein structure. For example, metalloproteases need a certain metal ion to fold correctly. If that particular metal ion is not readily available in the cell you are using, your protein will not fold correctly.
And there are also proteins that should fold in the same manner in both bacteria and human cells but they just don't to annoy you. I hate those proteins.
Mike Horwath
Oct 3, 2017, 10:09:10 AM10/3/17
to DIYbio
Yeah, "It depends"...one other big reason that mammalian proteins sometimes won't fold in bacteria is disulfide bonds between cysteines, which generally depend on oxidizing enzymes in the ER to form properly. There's kind of a hierarchy for trying different cell types to express human proteins--bacteria if possible, then yeast, then maybe insect cell line, then mammalian cells like chinese hamster ovary.
Mike
Hans Wilms
Oct 3, 2017, 7:04:48 PM10/3/17
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Is there a quick in silico way to determine whether correct folding of mammalian cells will happen in bacteria?
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Ravasz
Oct 4, 2017, 8:11:34 AM10/4/17
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Unfortunately we do not have the algorithms yet that can accurately predict protein structure from sequence. The current programs tend to get known domains mostly right, but they often fail with complete protein structures. Same for RNA. But in a few years this might change and then we'll also be able to tell if folding is different in bacteria compared to humans or other organisms.
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