What happens to a protein built from mutated RNA?

[icakeov]

I was wondering if anyone knew what happens to a protein that gets wrongly assembled due to a mutated RNA?

Does it just do a slightly different or very destructive action in the organism, or does the organism catch it and kick it out?

Also an extra side question:
Speaking of mutations of RNA, they can get mutated in many different ways, right? It can be from mutated gene that was inherited, or a mutation that happened in the gene in the meantime (can that happen?), or the RNA transcription might have had a mutation? Right?

Many thanks!

 

[Asteropaeus]

You mean mutated DNA? The question first is if the protein gets made.

Before I try to fill pages to explain exactly what happens and exactly what can go wrong at each step, can you rephrase your question?
What step exactly are you talking about? If you mean RNA, what RNA do you mean?

Also, do you have a certain protein in mind? Because how damaging it is to a cell depends a lot on the protein in question.

A mutation may be unique to a single DNA or mRNA molecule. A single chromosome may have a mutation, mRNA may be transcribed containing a mutation. But that is not going to be very impactful because that means that out of the millions of proteins, only one of those is going to have a different amino acid, assuming the mutation is a substitution point mutation that changes the codon code.

 

[icakeov]

Thanks so much for your reply!

You clarified so much already. I mainly had in mind the transcription process containing a mutation, and I understand that in that case, that one amino acid would be buried within the millions of other proteins that would have been produced without the mutation. I was wondering what happens to that one, wrongly made amino acid? (And yes, providing that it is actually produced in the first place.) And I didn't have any specific protein in mind, I was wondering if in general there are certain processes that happen when an event like this occurs with amino acids.

Similarly, if the DNA (gene) itself is mutated and manages to still successfully make proteins that either perform similar functions to the "original" protein that was supposed to be made, or if they produce a protein that perhaps does a harmful action, or some random action, or doesn't do anything? Does the cell track down these proteins and get rid of them somehow? Or does the protein just continue to do it's function because the cell thinks it "belongs" there?

Or am I thinking about all this wrongly? :) It's a fairly new subject matter and I am hoping to make sense out of it

 

[Asteropaeus]

When you are talking about transcription, there are no amino acids(yet). In Eukaryotes, you have pre-mRNA. Part of the genomic DNA is transcribed by RNA polymerase, that have less proofreading activity than DNA polymerase, making them faster.

Next, the pre-mRNA is spliced. If a mutation occurs at the splice sites, the mRNA can contain non-coding sequences and lose coding sequences. If there is a premature stop codon, the protein will be truncated. You get half of the correct protein. It will likely not fold the way it did as part of the original protein.
If there is an insertion or deletion, there will be a frame shift, and all amino acids will be different. You get a random protein.
A mutation can also change the expression of the protein. This is regulated on several levels, including on how much protein is produced from mRNA.

If one amino acid is changed, one amino acid changes. This usually has no effect at all, as not all amino acids in a protein are important and many mutations can exchange one amino acid for a similar one. Still, single amino acid mutations can make a protein not fold properly, not able to carry out it's intended function, make the proteins aggregate, causing fibers that disrupt the cell.

A single mRNA only has a limited life time. It will be translated 0 to 100,000 times. Then the mRNA is broken down and the mutation is lost.

All protein are recycled over time, using ubiquitin, proteases and lysosomes. Protein synthesis and degradation need to be in balance. So both happen at equal rates.

The amount of mutant proteins from a somatic mutation in DNA or mRNA is usually small. Still somatic mutations can happen and can cause disease; ie cancer.
Misfolded protein diseases also exist. For those, you don't even need a mutant protein.


Antibodies can recognize mutant proteins. Very early on in the embryo, all immune cells that make antibodies that bind to self protein are eliminated. So the immune system may recognize mutant protein, as it indeed does with cancer.
Usually mutant protein will just float around in the cell and be harmless. Remember that there are two copies of each allele. So there is a backup. Half the protein made is functional, the other half is mutant. If this is a germline mutation, having half the protein you normally have in all cells can cause a different phenotype or disease. Some mutations are dominant. You function fine/have the non-mutant phenotype as long as you have one good copy.

 

[icakeov]

Translated up to 100,000 times! I didn't know that!

Just to make sure I got it all right: Mutations do happen very rarely. And when they do, they don't necessarily get "caught" and "discarded" for not being properly built and can do wrong functions in the body, even causing cancer, etc. Until, eventually, over time, they get recycled.

Also, there is the whole side of gene alleles that might have been mutations in the past, but they code for the same (or similar?) protein. So essentially, this wouldn't be considered a "mutation" in a negative sense, but more a different expression of a gene to, for example, color our eyes differently.

 

[Asteropaeus]

A cell has about 10^7 to 10^10 molecules of protein. The 100,000 is the upper number. A 1000 of mutant proteins is not a whole lot. They need to have a special toxic property to be harmful. Merely them being nonfunctional during one mRNA isn't meaningful.


Everything is mutant when compared to something else. A cell or living organism can use several tricks to figure out what is 'good' and what is 'bad'. Apart from the genome copy it has, the human adaptive immune system, there are also other immune systems like CRISPR/cas9, gene silencing using RNAi or siRNA systems.

Having excess bad protein is a real weak spot of cells. But ubiquitin is the main discovery on how cells do try to handle this.

Mutations in the genome can be caught. Read up on (proto-)oncogenes or dna repair; if they break they can make cancer more likely. Some play a role in preventing mutations or cleaning up mutant cells.

It should be easy to recognize that to check all 10^10 protein in a cell using those same 10^10 proteins is not really a solvable problem.

You can't really check individual misfolded protein among 10^10 other protein. So most control happens on the DNA level. Or all the way on the cell level. If a cell is filled with lots of bad protein, of course that can be detected(MHC, antibodies). Usually not on the protein level. That would be a hard problem to solve, to somehow check the same of 10^10 proteins as they float in the cell.

 

[icakeov]

You're totally answering my question! Thanks so much Asteropaeus!
To sum it all up, few random small mutations in the production of proteins won't make a big effect with millions/billions of proteins floating around.
But if a cell contains a gene that creates way too many dysfunctional proteins, then the immune system will either silence the gene or dissolve the numerous dysfunctional proteins.

 

[Ygggdrasil]

Mutated proteins, proteins containing an amino acid substitution somewhere in their sequence, can have a number of different effects. Sometimes, these mutations cause no effect, and the protein is capable of functioning just fine. Sometimes, the mutation will destabilize the protein and cause it to misfold. Misfolded proteins are usually recognized by protein quality control machinery and degraded. Some mutations create stable, but non functional proteins. These non-functional proteins can sometimes be tolerated by the cell (as long as there are plenty of functional copies of the protein around), but sometimes these non-functional proteins can exert a dominant-negative effect. For example, if a protein assembles into a complex with four copies of the protein, and all four copies need to be active for the complex to work, a non-functional copy can act as a "poisoned" subunit, and prevent the other three copies of the protein from functioning correctly.

There are also a variety of mRNA surveilance pathways for identifying mRNAs containing errors. For example, many errors can introduce premature stop codons into mRNAs. In these cases, the ribosome stalls prematurely and the cell recognizes these stalled ribosomes, initiating a pathway that will recycle the stalled ribosome and degrade the mRNA containing the premature stop codon.

 

[icakeov]

Thanks Ygggdrasil!
So there is even the process that aborts the building of a protein if a faulty mRNA is detected.

 

[Ygggdrasil]

Thanks Ygggdrasil!
So there is even the process that aborts the building of a protein if a faulty mRNA is detected.

Yes, though the mRNA surveilance pathways cannot detect all types of faulty RNAs (it will mostly detect those that have been damaged in some way or have not been spliced correctly).