(From left) Ling Qi, Liangguang Leo Lin, and Ahmad Jomaa
Scientists at the University of Virginia School of Medicine have unveiled the first high-resolution structure of a central protein quality-control complex in human cells, illuminating how its malfunction drives disease. Their work, published in Nature Communications, provides fundamental insights into how cells maintain protein health and offers a framework to understand disease-causing mutations in the quality-control machinery that underlies disorders ranging from neurodevelopmental syndromes to metabolic dysfunction.
Cells rely on a meticulous system inside the endoplasmic reticulum (ER) to recognize and dispose of misfolded or damaged proteins — a process known as ER-associated degradation (ERAD). At the heart of this process is a core molecular machine composed of the proteins OS9, SEL1L, and the ubiquitin ligase HRD1. Until now, the exact architecture of this complex and how disease mutations impair its function has been poorly understood.
Using cutting-edge cryo-electron microscopy, the research team determined the three-dimensional structure of the complete human OS9-SEL1L-HRD1 ERAD core complex. The structure reveals how SEL1L and OS9 form a “claw-like” assembly that grips misfolded proteins in the ER lumen, while HRD1 spans the membrane to catalyze tagging of these flawed proteins for destruction.
Importantly, the study also identifies how pathogenic mutations — including changes in SEL1L and HRD1 found in patients — destabilize the complex and impair its quality-control function, offering a structural explanation for their role in human disease.
Key findings include:
- Revelation of the dimeric architecture of the human ERAD core complex and how its components collaborate to recognize and eliminate aberrant proteins.
- Demonstration that mutations at critical interfaces disrupt assembly and function, providing direct links between structure and disease mechanisms.
- A structural platform to help explain how quality-control defects contribute to conditions including neurodevelopmental disorders, immune dysfunction, and metabolic disease.
“This structure fills a critical gap in our understanding of cellular protein quality control and highlights how genetic variants can compromise cellular fitness,” said first and co-senior author Liangguang (Leo) Lin, PhD, research assistant professor of molecular physiology and biological physics.
“By illuminating the physical basis of ERAD function and dysfunction, we lay the groundwork for targeted efforts to understand — and potentially therapeutically address — diseases tied to this machinery,” said co-senior authors Ahmad Jomaa, PhD, assistant professor of molecular physiology and biological physics, and Ling Qi, PhD, professor and chair in the UVA Department of Molecular Physiology and Biological Physics.
The research was led by first author Liangguang Leo Lin, PhD, along with co-authors Emir Maldosevic and Linyao Elina Zhou in the Qi and Jomaa laboratories at UVA. It was supported by the NIH, the Searle Scholars Program, American Cancer Society, The Owens Family Foundation, and other funding sources.
Read the article in Nature Communications: https://www.nature.com/articles/s41467-026-68777-7
Filed Under: Research