In a groundbreaking discovery, researchers from Caltech, the University of Konstanz, and ETH Zurich have uncovered a critical mechanism that governs the modification of nascent proteins, which are essential for cellular function. The study reveals that a small chaperone protein complex, known as the nascent polypeptide-associated complex (NAC), plays a pivotal role in regulating protein production by orchestrating the activity of key enzymes during the early stages of protein synthesis.
Proteins, the fundamental building blocks of life, are assembled from amino acids according to the instructions encoded in our DNA. However, this process involves more than just stringing together amino acids. As nascent proteins emerge from the ribosome, the cellular machinery responsible for protein synthesis, they undergo crucial modifications that determine their final structure and function. Until now, how these modifications are coordinated has remained largely a mystery.
The research team has identified NAC as a master regulator in this process, particularly in overseeing two specific protein modifications that occur in about 40% of all mammalian proteins. NAC not only recruits the necessary enzymes to the ribosome but also ensures they act precisely at the right time and place, preventing potential cellular stress and misfolding of proteins.
“The essential chaperone NAC has been implicated in a wide range of cellular processes,” said Shu-ou Shan, Altair Professor of Chemistry at Caltech and the study’s corresponding author. “Our findings reveal that NAC is not just a simple chaperone but a high-order master regulator of protein production in the cell.”
The study, published in the journal Nature, focuses on two critical modifications orchestrated by NAC: the removal of the first amino acid, methionine, from the nascent protein, and the subsequent attachment of an acetyl group to the protein’s newly exposed end. These modifications, occurring at the ribosome’s tunnel exit, are essential for determining the protein’s stability, folding, and interactions.
The researchers discovered that NAC is instrumental in positioning two enzymes—MetAP1, which removes methionine, and NatA, which acetylates the protein—at the ribosome’s exit tunnel. NAC also facilitates the release of NatA from its inhibitory protein, HYPK, ensuring that acetylation occurs precisely where and when needed.
“By elucidating how NAC controls these processes, we’ve gained insights into how dysregulation of protein modification can lead to diseases such as cancer and Parkinson’s,” said Elke Deuerling, professor of molecular microbiology at the University of Konstanz and a co-author of the study.
The study also suggests that NAC’s role extends beyond these two enzymes, potentially acting as a broader molecular control hub that ensures nascent proteins access various cellular components as they leave the ribosome.
“This discovery opens new avenues for understanding how protein modifications are regulated and how their dysregulation can contribute to disease,” said Martin Gamerdinger, a co-author from the University of Konstanz. “In the long term, this could pave the way for developing novel therapeutic approaches.”
The research involved significant contributions from additional Caltech researchers, Alfred M. Lentzsch and Sowmya Chandrasekar, as well as Denis Yudin, Alain Scaiola, and Nenad Ban from ETH Zurich. The paper, titled “NAC guides a ribosomal multienzyme complex for nascent protein processing,” provides a detailed look into the intricate molecular mechanisms that maintain cellular health and function.
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