It’s not easy – especially when you’re a mere chemist – to picture what’s really going on inside a cell. The sorts of pictures that most of us tend to use (two blobs to represent a ribosome, little snakey line curving out from it to represent a new protein) are helpful memory devices, but have very little to do with reality.
Just to pick one example, I’ve had to update my thinking the last few years as the importance of condensates has become more apparent, for example: the inside of the cell is constantly experiencing the formation (and dissolution) of all sorts of tiny nonmixing liquid droplets of concentrated proteins and RNA species, like a bottle of salad dressing a few seconds after you shake it up, but without the further separation into two bulk phases. Here’s another: that mental picture of a ribosome I just mentioned doesn’t get across the way that proteins that are destined for a home in a membrane (the cell’s plasma membrane itself, or the ER or what have you) generally get recognized by their N-terminal sequences while the protein is still coming out of the ribosome. The whole shebang gets hauled over to its new home with the ribosome paused until it gets situated and protein synthesis starts up again.
There are plenty of other co-translational events going on as well. Many proteins that have an important partner actually have regions that bind to some part of the translation machinery (such as the mRNA of their partner-protein-to-be), so that they’re waiting right there while said partner emerges from the ribosome. And don’t get the idea that all of this is happening perfectly all the time, either – all of these mechanisms are constantly throwing errors, and that ribosomal complex is surrounded by other proteins whose job is to constantly look for trouble and try to correct it. I am reminded of a college classmate of mine who had a summer job – briefly – at a bottling plant in Alabama. There was a part of the line where the bottles narrowed down to a single file for some step (capping or labeling, I suppose) and this would occasionally jam up when two of them did the perfectly timed slapstick jammed-in-the-door maneuver on their way into the single file part. My friend’s job, as he described it, was to watch for these events and to reach in and straighten them out, which had to be done with speed and precision and which could happen as often as two or three times per eight-hour shift. He made it through two or three days of that before deciding to seek other employment, but the quality control proteins have no other options.
How about transcription? You might have a model of a few ovals and circles (the RNA polymerase complex) smoothly ratcheting along a strand of DNA. But in reality, many of those complexes take off in the wrong direction and stall. And they will rachet backwards on purpose if a base polymerization error is detected, although that process sometimes stalls out, too. This “backtracking” has a whole suite of correction mechanisms on top of it. At any rate, the time a Pol II complex spends actually transcribing DNA and the speed at which it does so seem to be pretty variable.
But we don’t have to get into such details in order to see how “off” our perceptions are. I, and probably many others, have a mental picture of an mRNA sequence being read out and transcribed into a larger protein, but that can’t be right. And it isn’t! In reality, the mRNAs are, on average, about ten times the size of proteins themselves. This feels wrong to us, because we’re used to our own preferences for algorithmic compression: blueprints are smaller than houses, but not inside the cell. Of course, when we’re talking about RNAs, we have to remember that those blueprints themselves are folded up to make small houses of their own – and if you’d like more metaphors of that kind, I have plenty of ’em.
So we should stay humble when we start talking about what’s going on inside the cell. It’s weird in there, and it’s important not to confuse our diagrams and shorthand with reality. Under the current coronavirus conditions, that means that when someone starts lecturing you confidently about exactly what’s going on (you see, the zinc opens the channels and then the hydroxychloroquine goes in and. . .), keep in mind how little we actually understand. . .