Capturing the right enzymes at the right moment
But this is not all that NAC can do. In their new study, just published in Science Advances, Ban and his colleagues from the Universities of Konstanz, Germany, and Caltech reveal a previously unknown function: how NAC ensures the correct chemical modification of the histones H4 and H2A while they are still being synthesized.
Histones are small, abundant proteins that must be produced rapidly when cells prepare for division. Eight histones assemble into so-called nucleosomes, around which DNA is wrapped and thereby compacted. Chemical modification of these proteins while they are being synthesized is crucial for proper chromosome function, and errors can contribute to diseases such as cancer.
In their study, the researchers show that NAC brings two enzymes to the ribosome to first remove the first amino acid from the histone protein and then to modify the newly exposed end with an acetyl chemical group. Because histones are assembled very rapidly, these two processing steps must occur in the correct sequence and almost instantaneously.
“For histones, the time window for modifications is incredibly tight because their protein chains are very short,” explains first author Denis Yudin, a doctoral student in Nenad Ban’s lab. “NAC ensures that the right enzyme is at the right place at exactly the right time.”
Structural insights open possibilities for therapies
Other studies show that the enzyme that modifies histone proteins with acetyl group, NatD, is frequently overproduced in certain types of cancer, altering gene regulation and promoting tumor growth. NAC’s control over the access of the enzyme NatD to the ribosome could therefore provide new insights into tumor biology.
Detailed structural information about NAC and the enzymes it recruits, including how NatD binds to one of NAC’s flexible arms, could open up new therapeutic strategies. These include drugs that block NatD’s interaction surface or prevent its recruitment to translating ribosomes. Other diseases that result from faulty processing during ongoing translation could also benefit from these findings.
A fundamentally changed understanding of protein biosynthesis
“The new findings change our view of protein synthesis,” explains Ban. “They show how coordinated and dynamic the processes at the ribosome are, and how a small complex at the tunnel exit sets the pace for a large fraction of protein production in our cells.”
The insights also mean that future efforts to achieve a deeper understanding of protein formation must necessarily take NAC’s function into account. “They also point to a larger field of research emerging in my lab: the question of how NAC integrates co-translational targeting, enzymatic modification, protein folding, and assembly into a coordinated system.”
In this sense, NAC behaves less like a passive scaffold and more like a molecular gatekeeper. “By selectively opening or closing access to the ribosome depending on the type of protein that is being synthesized NAC acts like a remarkably precise sorter that nonetheless fully obeys the principles of thermodynamics,” says the ETH professor.