ETH Zurich researchers have identified a new function for the nascent polypeptide–associated complex (NAC), a protein complex involved in the early stages of protein synthesis. The study, recently published in Science Advances, reveals that NAC not only coordinates the initial processing and transport of newly formed proteins but also plays a role in modifying histone proteins as they are synthesized.
Ribosomes, which assemble amino acids into peptide chains during translation, rely on NAC to ensure these chains are properly processed before folding into functional proteins. As soon as a new protein emerges from the ribosome, enzymes may remove its initial amino acid or attach chemical groups that determine its cellular destination. These steps are essential for most proteins and require precise coordination.
NAC is composed of two proteins forming a core with four flexible extensions. One extension anchors it to the ribosome while the others interact with various enzymes and molecular factors needed for protein production. According to research led by ETH biologist Nenad Ban, "NAC ensures that the right enzyme is at the right place at exactly the right time," said Denis Yudin, first author and doctoral student in Ban's lab.
The team found that NAC recruits two specific enzymes to modify histones H4 and H2A during their synthesis. Histones are crucial for DNA packaging within cells and must be rapidly produced when cells divide. Errors in their modification can lead to diseases such as cancer.
Other studies indicate that NatD, an enzyme responsible for acetylating histone proteins, is often overproduced in certain cancers, which affects gene regulation and promotes tumor growth. By controlling NatD’s access to ribosomes, NAC could offer new perspectives on tumor biology.
Detailed structural insights into how NAC interacts with these enzymes suggest potential therapeutic strategies—such as drugs designed to block NatD’s recruitment or interaction with translating ribosomes—that could address diseases caused by faulty protein processing.
Ban emphasized that future research into protein formation should consider NAC’s integrative role: "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."
Describing its function further, Ban added: "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."
