New insights into how a molecular gatekeeper controls early protein modification

For years, ETH researchers have been investigating a molecular complex that plays a key role in protein synthesis. They have now discovered that this complex also contributes a crucial function in ensuring that our DNA is properly processed and “packaged”. 

The protein factories in our cells – so-called ribosomes – have a central task: during a process known as translation, amino acids are linked together according to messenger RNA, forming a growing peptide chain that later folds into a functional protein. 

However, before a newly emerging protein can even begin to fold, it must be processed and transported to the correct location within the cell. As soon as it emerges from the ribosome, enzymes can remove its initial amino acid, attach small chemical groups, or determine to which cellular compartments the protein should be sent. These activities already take place during translation and are essential for the correct function of most proteins. And this requires a coordinator. 

What is NAC and why is it important? 

This coordinator is a protein complex known to experts as the nascent polypeptide–associated complex (NAC). Without NAC, these early modifications become inefficient or erroneous.

Since its discovery around 30 years ago NAC's functions have remained unclear. However, recent work from the laboratory of ETH biologist Nenad Ban shows how NAC regulates protein maturation by recruiting specific enzymes precisely when and where they are needed. 

NAC sits exactly at the point where newly synthesized polypeptide chains emerge from the ribosome, making it ideally positioned to coordinate the earliest processing steps. 

NAC consists of two proteins that form a central ball-shaped core with four highly flexible extensions, giving it an octopus-like appearance at the molecular level. One of these arms anchors NAC to the ribosome. The other three can bind a wide range of enzymes and other molecular factors involved in protein production, including a molecule that directs proteins specifically for insertion into membranes.
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. 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." 

Nenad Ban, Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zürich

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.