As an ex biomedical researcher I was trying to think what protein I should enter and see, and couldn't come up with a protein that I know of, that didn't have a structure already (at least a crude one). That is, we roughly know how most known important proteins look like. This is an amazing tool, and will he indispensable in labs (I'll expect any lab to use this site at least once a year?) But it's not as transformat…
Do we really know the structure of every protein that assembles into a human cell?
As an ex biomedical researcher I was trying to think what protein I should enter and see, and couldn't come up with a protein that I know of, that didn't have a structure already (at least a crude one). That is, we roughly know how most known important proteins look like. This is an amazing tool, and will he indispensable in labs (I'll expect any lab to use this site at least once a year?) But it's not as transformat…
Do we really know the structure of every protein that assembles into a human cell?
Interesting that they're porting it to other organisms. Different organisms have variations in ribosomes, post translational modifications and even tRNA repertoire. So it's not a guarantee that two identical DNA sequences will give identical proteins in two different organisms.
Shouldn't matter? Protein folding is based on the laws of physics after all. If DNA sequences folds differently in different organisms then an external factor is missing.
While the laws of physics remain the same, the folding machinery between species varies to some degree. Protein folding is determined by the unique environment/machinery of a cell. A concrete example is disulphide bonds (S-S, ex cystein-cystein) that require a certain pH to form. The primary pathways of disulphide-bond formation are localized in the endoplasmic reticulum (ER) of eukaryotic cells and the periplasmic space of prokaryotic cells. So two complete different mechanisms to end up with the same bond (protein structure) depending on the organism.
Interesting that they're porting it to other organisms. Different organisms have variations in ribosomes, post translational modifications and even tRNA repertoire. So it's not a guarantee that two identical DNA sequences will give identical proteins in two different organisms.
??? Unless you jump from eukaryotes to archea these are not real concerns. Most PTM markers are very conserved.
I'd say the jump from eukaryotes to procaryotes is a realistic scenario in recombinant DNA technology.
I have some experience with recombinant yeast and PTMs. Degree of glycosylation actually vary a lot depending on strain used and has a huge effect of protein activity. And of course these PTMs affects the crystal structure.
Shouldn't matter? Protein folding is based on the laws of physics after all. If DNA sequences folds differently in different organisms then an external factor is missing.
While the laws of physics remain the same, the folding machinery between species varies to some degree. Protein folding is determined by the unique environment/machinery of a cell. A concrete example is disulphide bonds (S-S, ex cystein-cystein) that require a certain pH to form. The primary pathways of disulphide-bond formation are localized in the endoplasmic reticulum (ER) of eukaryotic cells and the periplasmic s…
Outside of missing post translational modifications, can you give a concrete example of a protein that is known to fold differently in different species, not counting, say, stuff getting sent to the garbage bin of inclusion bodies due to the stress of overexpression? My understanding (7 years of grad school researching protein folding in the ER) is that outside of some rare corner and disease state cases, folding is pretty much binary event, and if it weren't for most cases the low delta g difference between isoforms would be just as easily overcome over the course of environmental changes in a single individual as "between different species" namely having a deterministic outcome is important for through-time robustness.
Quick question, please excuse my ignorance, but is there a way to extrapolate sequence from structure? In other words, can we design proteins and calculate the sequence required to make it?
It's hard but people do it! This is the field of "protein engineering".
This is awesome! When they announced CASP results a few months ago, I was wondering if AlphaFold will be accessible as an API, where you can submit a protein id or a sequence and get back a 3D structure. This database is basically that, except it's free & open to the public. Major props!
As an ex biomedical researcher I was trying to think what protein I should enter and see, and couldn't come up with a protein that I know of, that didn't have a structure already (at least a crude one). That is, we roughly know how most known important proteins look like. This is an amazing tool, and will he indispensable in labs (I'll expect any lab to use this site at least once a year?) But it's not as transformat…
Do we really know the structure of every protein that assembles into a human cell?
From their abstract:
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After decades of effort, 17% of the total residues in human protein sequences are covered by an experimentally-determined structure1. Here we dramatically expand structural coverage by applying the state-of-the-art machine learning method, AlphaFold2, at scale to almost the entire human proteome (98.5% of human proteins). The resulting dataset covers 58% of residues with a confident prediction, of which a subset (36% of all residues) have very high confidence.
The metric they use (residues) is a bit unusual (I would have used number of proteins instead), but I assume they wanted to account for ambiguity (such as proteins with partial structures).
As an ex biomedical researcher I was trying to think what protein I should enter and see, and couldn't come up with a protein that I know of, that didn't have a structure already (at least a crude one). That is, we roughly know how most known important proteins look like. This is an amazing tool, and will he indispensable in labs (I'll expect any lab to use this site at least once a year?) But it's not as transformat…
Do we really know the structure of every protein that assembles into a human cell?
One of the reasons we don't have them all is that individual genes can encode for multiple protein isoforms through alternative splicing. AlphaFold was only run on one. Otherwise, there's lots of important biochemical/biophysical processes that impact structure, as cells are only about 50% protein by weight.