Proteins are long chains of amino acids that must fold into precise three-dimensional structures before they can perform their functions. This folding process is governed by a complex balance of chemical forces, including hydrogen bonding, hydrophobic interactions, electrostatic attraction and the movement of water around the protein surface. A small change in temperature, pH, genetic sequence or chemical environment can destabilize that balance. When a protein fails to maintain its native structure, it may partially unfold and expose normally hidden regions. These exposed surfaces can interact with equivalent regions on other molecules, allowing the proteins to associate into oligomers, fibers and eventually amyloid deposits. Such assemblies are central features of several neurodegenerative and cardiovascular diseases, but their formation is not a simple chemical accident. It is a dynamic process that can potentially be redirected with carefully designed molecules.

Kelly’s research has focused on understanding that process at a level detailed enough to reveal where therapeutic intervention is possible. His laboratory has combined organic chemistry, biophysics, structural biology and cell-based approaches to examine how proteins move between folded, unfolded and aggregated states. Rather than viewing misfolding as a single catastrophic event, the work has treated it as an energy landscape containing multiple intermediate forms. Some intermediates may be short-lived and harmless, while others can act as especially efficient seeds for further aggregation. Identifying which molecular states initiate disease is essential because a treatment may need to stabilize the healthy protein before it begins to unravel, block the formation of toxic intermediates or prevent already formed assemblies from damaging cells. This framework has helped shift protein-misfolding research from observation toward rational therapeutic design.

One of Kelly’s most influential achievements involved transthyretin, or TTR, a protein produced primarily by the liver and responsible for transporting thyroxine and retinol-binding protein in the bloodstream. TTR normally circulates as a tetramer made of four identical subunits. In hereditary forms of transthyretin amyloidosis, mutations can weaken the interactions holding the tetramer together. The complex may then dissociate into individual subunits, which can partially unfold and assemble into amyloid fibrils. These fibrils accumulate in tissues, damaging peripheral nerves in transthyretin amyloid polyneuropathy and impairing the structure and function of the heart in transthyretin amyloid cardiomyopathy. Even the normal, nonmutated protein can become amyloidogenic with age, making the disease relevant beyond inherited mutations. Kelly’s studies clarified that tetramer destabilization is a critical early event and therefore a promising point for intervention.

That mechanistic insight contributed to the development of tafamidis, the active pharmaceutical ingredient in Vyndamax and Vyndaqel, medicines approved by the U.S. Food and Drug Administration for transthyretin-related disease. Tafamidis functions as a kinetic stabilizer: it binds to thyroxine-binding sites within the TTR tetramer and makes dissociation less likely. The distinction between thermodynamic and kinetic stabilization is important. A drug does not necessarily need to make the folded state the only energetically favorable state; it can instead slow the rate at which the protein reaches a disease-associated state, extending the lifetime of the functional tetramer. By reducing the supply of misfolded TTR subunits, the treatment can limit the production of new amyloid material. The approach demonstrates how defining the molecular sequence of disease can reveal a practical treatment strategy that operates before irreversible tissue damage becomes extensive.

The development of TTR stabilizers also illustrates why protein aggregation cannot be addressed solely by searching for compounds that dissolve visible deposits. Amyloid fibrils may represent the endpoint of a much longer process, and the most harmful species can arise earlier, when small assemblies interact with cell membranes or disrupt intracellular pathways. A drug that targets the earliest destabilizing transition may therefore have greater impact than one aimed at mature deposits. Kelly’s research helped establish this preventive logic by linking the behavior of individual protein molecules to disease progression in patients. It also provided a general model for studying other amyloid disorders, in which the identities of the proteins differ but the underlying challenges—conformational instability, intermolecular association and tissue-specific toxicity—are conceptually related. The work has made protein chemistry a direct engine of therapeutic discovery.

The European Academy of Engineering, founded in Sweden in 1992, brings together experts from a broad range of technical disciplines and advises on issues involving policy, public health and education. Its members are elected by peers across 13 engineering classes, each representing a specialized area. Kelly’s election recognizes a career in which discoveries traditionally associated with chemistry have produced consequences for biomedical engineering, drug development and clinical care. His honors include the Canada Gairdner International Award, election to the U.S. National Academy of Sciences, the Wolf Prize in Chemistry in 2023 and the Breakthrough Prize in Life Sciences in 2022, in addition to numerous other distinctions. Together, these awards reflect the unusual reach of research that began with questions about molecular structure and ultimately helped produce a medicine for a life-threatening protein-aggregation disorder.

Kelly’s election arrives as scientists increasingly seek therapies that modify the physical behavior of disease-linked proteins rather than merely treating symptoms after damage has occurred. Advances in cryo-electron microscopy, nuclear magnetic resonance, mass spectrometry and computational modeling are making it possible to observe unstable conformations and transient protein assemblies with growing precision. These tools may reveal additional opportunities to stabilize vulnerable proteins, remove harmful species or correct the cellular systems responsible for protein quality control. The broader lesson of Kelly’s work is that understanding how a protein fails can be as important as understanding how it functions when healthy. By tracing the molecular steps that connect folding errors to human disease, researchers can convert a seemingly microscopic chemical event into a clear therapeutic target—and, in some cases, into a treatment capable of changing the course of illness.

Subject of Research: Protein folding, protein misfolding and amyloid aggregation, with a focus on transthyretin amyloidosis and therapeutic protein stabilization.

Web References: Jeffery Kelly — Scripps Research

Image Credits: Scripps Research

Keywords

Protein folding; neurodegenerative diseases; cardiomyopathy; transthyretin amyloidosis; amyloid aggregation; protein misfolding; biomedical engineering; tafamidis; Scripps Research; Jeffery Kelly

The ER, a membrane-bound organelle often described as the cell’s protein factory, is where roughly one-third of all human proteins, including nearly 7,000 unique molecules, begin their complex folding journey. This environment is chaotic and crowded, filled with nascent polypeptides, folding enzymes, and molecular chaperones. Among these, chaperones function as specialized molecular guardians that assist proteins in reaching their native, functional conformations or, failing that, direct irreparably misfolded proteins toward degradation pathways. Defects in this quality control system can trigger a cascade of cellular malfunctions, implicated in diseases such as cystic fibrosis, emphysema, and Alzheimer’s.

Despite the vital role chaperones play, a fundamental question has persisted: how do these molecular caretakers discriminate between properly folded and misfolded proteins amidst the entropic sea of the ER lumen? The answer, as detailed by Hebert and his team, lies in a sophisticated carbohydrate-based “glyco-code” inscribed on proteins themselves via attachment of specialized sugar structures called N-glycans. These N-glycans act as molecular zip codes, precisely positioned on the protein’s surface, encoding vital information that directs the chaperone machinery’s interactions and decisions.

The concept of a glyco-code marks a paradigm shift from traditional views that have primarily focused on the polypeptide chain as the sole bearer of folding information. Instead, the review artfully illustrates how carbohydrate moieties, especially N-glycans, serve as dynamic modulators of protein destiny within the ER. This code utilizes sugar patterns, sugar-processing enzymes, and lectin chaperones—carbohydrate-binding proteins that can “read” the sugar code—to guide substrate folding, sorting, and degradation. The interplay between these elements ensures only correctly folded proteins proceed toward secretion or membrane integration, while aberrant proteins are sequestered or targeted for destruction.

Central to this glyco-code is the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT), described in prior work involving Hebert’s research group and highlighted in the current review. UGGT functions as a folding sensor by recognizing misfolded regions and selectively reglucosylating N-glycans, thereby generating a recognizable signal for ER-resident lectin chaperones such as calnexin and calreticulin. These chaperones engage in cycles of binding and release, giving proteins multiple opportunities to achieve their native fold, a process critical to maintaining cellular proteostasis.

Moreover, the review elucidates the intricate biochemical pathways that regulate how N-glycans are attached co-translationally and post-translationally to asparagine residues within consensus sequences on nascent polypeptides. The precise positioning and structural diversity of these glycans significantly influence the affinity and specificity of chaperone interactions. This spatially encoded information facilitates compartmentalized maturation processes and ensures the fidelity of sorting mechanisms that traffic proteins from the ER to the Golgi apparatus and beyond.

A remarkable aspect highlighted is the dual role of the glyco-code: not only does it assist in protein folding quality control, but it also functions as an addressing system that dictates intracellular trafficking pathways. Lectin chaperones interpret the glyco-code to direct folded proteins toward their ultimate cellular destinations, whereas misfolded or unassembled proteins are recognized by ER-associated degradation (ERAD) machinery, which retrotranslocates them for cytosolic proteasomal degradation.

The work by Hebert, and elucidated by his last graduate student Kevin Guay, also stresses the implications for human health. Many protein conformational diseases are rooted in failures of this glyco-code-based quality control, where either the recognition or processing of N-glycans is impaired, leading to accumulation of toxic protein aggregates or loss of essential functional proteins. Therapeutic strategies targeting components of this glycosylation-dependent chaperone network are increasingly attractive for treating diseases linked to protein misfolding.

In essence, the review synthesizes decades of biochemical, structural, and cellular biology research into a comprehensive framework that redefines our understanding of how protein folding and quality control are intricately regulated by N-glycans. This new vision fosters a broader appreciation that genetic information encoded in DNA extends beyond sequence alone, encompassing a multilayered molecular code integrated within protein glycosylation patterns.

Hebert’s magnum opus not only honors his lifetime contributions to the field but also establishes a foundation upon which future studies will build, aiming to fully decipher the glyco-code. This, in turn, promises to unlock novel therapeutic avenues and advance our ability to manipulate protein folding processes in disease and biotechnology.

The collaborative nature of this work, involving UMass Amherst researchers and their deep expertise in enzymology, structural biology, and cellular machinery, stands as a testament to the enduring quest to unravel the complexities of life at the molecular level. As chaperone biology evolves, embracing the glyco-code paradigm will be pivotal in transforming molecular medicine and our grasp of cellular homeostasis.

With the publication of this comprehensive review in Nature Reviews Molecular Cell Biology, the scientific community gains critical insight into an elegant, carbohydrate-guided proofreading system. Ultimately, this work reinvents the classic narrative of genetic coding and protein folding by placing glycosylation—not just amino acid sequence—at the forefront of post-translational quality control.

Subject of Research: Protein folding quality control mediated by N-glycan-dependent chaperone systems within the endoplasmic reticulum.

Article Title: N-glycan-dependent protein maturation and quality control in the ER

Web References:
https://www.nature.com/articles/s41580-025-00855-y
http://dx.doi.org/10.1038/s41580-025-00855-y

Image Credits: UMass Amherst

Keywords: Protein folding, N-glycans, glyco-code, endoplasmic reticulum, molecular chaperones, UGGT, calnexin, calreticulin, ER-associated degradation, protein quality control, secretome, biochemistry, molecular biology