(From left) Emir Maldosevic and Ahmad Jomaa, PhD
A recent study from the lab of Ahmad Jomaa, PhD, in the Department of Molecular Physiology and Biological Physics, reveals how the ribosome-associated chaperone NAC acts as a molecular gatekeeper to ensure proteins are delivered to the correct cellular destination. Many proteins must be accurately directed to specific compartments, such as mitochondria, the cell’s energy-producing structures, and errors in this process are linked to neurodegenerative diseases and cancer.
Using structural and biochemical approaches, Dr. Jomaa’s work identifies a conformational “switch” in NAC that selectively recognizes newly made mitochondrial proteins and prevents their misdirection to the endoplasmic reticulum. By restricting access of the signal recognition particle (SRP), NAC enforces targeting fidelity early during protein synthesis before errors can propagate. This study provides a mechanistic framework for how cells maintain protein localization accuracy and highlights the ribosome as an active decision-making hub in protein biogenesis.
“The ribosome is not just a passive machine. It actively decides where proteins go as they are being made. By uncovering how NAC acts as a gatekeeper, we’re beginning to understand how cells prevent targeting errors before they happen,” said Dr. Jomaa.
“This has important implications for diseases like neurodegeneration and cancer, where protein mislocalization if not cleared can have serious consequences.”
In a second study, the lab uncovers how a conserved sequence within mRNA encoding for the AMD1 enzyme regulates its own production through programmed ribosome stalling. AMD1 is a key enzyme in the synthesis of polyamines, small molecules required for cell growth and motility, whose dysregulation has been implicated in cancer. Structural analysis shows that a short segment of AMD1 forms a molecular “brake” inside the ribosome, temporarily halting protein synthesis at a precise stage. This pause likely allows cells to fine-tune how much AMD1 is produced, preventing imbalances in polyamine levels.
“This work reveals a fascinating layer of control encoded within proteins themselves. The ribosome can pause at precise moments to fine-tune protein production, which is essential for maintaining cellular balance,” Dr. Jomaa stated. The findings reveal a previously underappreciated strategy by which cells use sequences within proteins themselves to directly control the protein-making machinery, with broad implications for gene regulation, human disease, and new therapeutic interventions.
The NAC research was conducted in collaboration with the Shu-ou Shan lab at California Institute of Technology and the Qi lab at UVA. The AMD1 work involved collaboration with the Baranov Lab at University College Cork in Ireland. Both studies were spearheaded by Emir Maldosevic, a graduate student in the Jomaa lab.
“Emir drove these projects with remarkable creativity and rigor. He brought together structural biology, biochemistry, and cell-based approaches in a way that really allowed us to see these mechanisms come together. It’s been incredibly rewarding to watch him and this work develop,” said Dr. Jomaa. Emir is also the winner of this year’s BIMS Top Biophysics Student Award and the Michael J. Peach Outstanding Graduate Student Award.
Research in the Jomaa lab is supported by the National Institute of General Medical Sciences, the Searle Scholars Program, the UVA Cancer Center, and the Owens Family Foundation.
Jomaa lab research was published in the journal Science Advances and Nature Communications.