Scientists at the University of Arkansas have developed a more stable and biologically active form of human fibroblast growth factor 1, a signaling protein with important roles in cell growth, tissue repair and metabolism. The engineered molecule, described in a study published in the Biophysical Journal, carries a precisely designed charge-reversal mutation that changes how it interacts with heparin, a class of carbohydrate molecules that helps organize growth-factor signaling in tissues. The modification substantially improved the protein’s structural stability and increased its ability to stimulate cell proliferation, according to the researchers. The work could eventually support the development of new approaches for wound healing and metabolic disease, although the findings remain at the experimental stage and are not yet evidence of a treatment for patients.
Fibroblast growth factors, commonly known as FGFs, are among the body’s central communication molecules. They bind to specific receptors on the surface of cells and activate signaling pathways that regulate proliferation, differentiation, survival, migration and metabolism. These processes are essential from the earliest stages of embryonic development and remain important throughout adult life, particularly when tissues are damaged and must be rebuilt. FGF1, the protein examined in the new study, is found in many tissues and has been associated with wound repair and metabolic regulation. Its ability to encourage cells to multiply has also attracted interest as a potential means of accelerating regeneration in conditions where healing is impaired, including chronic diabetes.
That same biological power creates a fundamental challenge. In its natural form, FGF1 is structurally fragile and has a relatively short biological half-life, meaning that it loses activity quickly under physiological or experimental conditions. The researchers suggest that this instability may serve an evolutionary purpose. A growth factor that remained active indefinitely could promote excessive or uncontrolled cell division, potentially increasing the risk of abnormal tissue growth and cancer. The molecule’s limited lifetime may therefore help the body balance the need for regeneration against the dangers of unrestricted proliferation. For therapeutic development, however, the short-lived nature of native FGF1 makes it difficult to produce, store and deliver in a consistent way.
The Arkansas team spent more than a decade studying the three-dimensional architecture of human FGF1 and the molecular events that control its activity. Their work focused particularly on the region known as the heparin-binding pocket. Heparin and related sulfated molecules are abundant in the extracellular environment, where they can bind growth factors and influence their movement, stability and access to cell-surface receptors. In the case of FGF1, heparin binding is closely connected to the assembly of a signaling complex. When FGF1 interacts with heparin and its receptor, the resulting molecular arrangement helps initiate a cascade of intracellular signals that can alter gene expression and drive cell proliferation.
To examine these interactions, the scientists used advanced multidimensional nuclear magnetic resonance spectroscopy. NMR spectroscopy allows researchers to probe the behavior of atoms within a protein and reconstruct information about its shape, flexibility and molecular contacts in solution. Rather than providing only a static image, the technique can reveal how a protein fluctuates and how specific regions respond when another molecule binds. This was important for the Arkansas researchers because FGF1’s activity depends not only on its overall fold but also on the electrical properties of individual amino acids at its heparin-binding surface. By mapping these interactions, the team identified an opportunity to alter the protein’s behavior without destroying the structure required for biological signaling.
The key change was a mutation known as R126E. It replaces arginine at position 126, an amino acid carrying a positively charged side chain, with glutamic acid, which carries a negative charge under physiological conditions. Because heparin is highly negatively charged, positively charged regions of proteins commonly help anchor growth factors to it. Reversing the charge at this strategic location changed the electrostatic environment of the binding pocket. The result was not simply weaker binding, but a redesigned interaction that improved the protein’s stability and enhanced its proliferative activity in cellular experiments. The mutation effectively demonstrates how a single, rationally selected change in a protein’s surface chemistry can reshape its structural behavior and biological performance.
The researchers report that the engineered FGF1 retained its capacity to participate in the signaling processes required for cell proliferation while becoming more resistant to destabilization. That distinction is critical. A protein can be made more stable by introducing changes that inadvertently prevent it from recognizing its receptor or activating downstream pathways. In this case, the charge-reversal strategy appears to have preserved, and in measured experiments strengthened, the functions that make FGF1 biologically valuable. The findings provide a molecular explanation for how the heparin-binding pocket contributes to both stability and activity, while also offering a template for engineering other growth factors whose therapeutic potential is limited by rapid degradation or conformational instability.
The discovery has particular relevance to chronic wounds associated with diabetes and other metabolic disorders. High blood glucose, impaired blood flow, inflammation and defective cellular responses can slow the normal sequence of tissue repair, leaving patients vulnerable to persistent ulcers, infection and, in severe cases, amputation. A more durable form of FGF1 could one day be investigated as a way to support the proliferation and migration of cells involved in tissue regeneration. However, the engineered protein has not been established as a clinical therapy, and questions about delivery, dosage, immune responses, tissue specificity and long-term safety will require extensive testing. Because FGF1 stimulates cell growth, researchers must also carefully assess whether prolonged or poorly controlled activity could produce unwanted effects.
The study also points toward a broader metabolic application. Suresh Kumar Thallapuranam, the study’s corresponding author and a University Professor of chemistry and biochemistry at the University of Arkansas, said the work provides a foundation for what he describes as “super FGF.” According to Thallapuranam, that future direction involves metabolic properties that could help cells oxidize fatty acids and glucose and remove cholesterol, characteristics that might be relevant to obesity and related disorders. Those claims extend beyond the experiments reported in the current paper, which centered on the structural stability and activity of FGF1. Still, the ability to tune a growth factor’s molecular interactions through targeted engineering could allow scientists to develop variants with distinct biological functions rather than treating naturally occurring proteins as fixed entities.
The research was conducted largely by scientists from the University of Arkansas Departments of Chemistry and Biochemistry and Biomedical Engineering, with support from the National Institutes of Health. Thallapuranam also directs the Bioenergetics Core of the Arkansas Integrative Metabolic Research Center, where the team applies advanced biochemical and biophysical tools to biomedical questions. The charge-reversal strategy described in the study has been protected through a patent-related application, and one or more authors are listed as inventors on a related patent concerning engineered FGF compositions and their uses. The next stage will be determining whether the enhanced protein performs safely and effectively in increasingly complex biological models. For now, the study offers a detailed example of protein engineering in action: by changing one electrical feature in a growth factor’s binding surface, researchers have produced a version that is more stable, more active and potentially better suited for future therapeutic investigation.
Subject of Research: Cells
Article Title: Charge reversal in the heparin-binding pocket enhances the stability and activity of the human FGF1
News Publication Date: 4 August 2026
Web References: Biophysical Journal: https://www.cell.com/biophysj/fulltext/S0006-3495(26)00478-9
References: DOI: 10.1016/j.bpj.2026.06.037
Image Credits: Matt Reynolds
Keywords: Fibroblast growth factor 1, FGF1, protein engineering, heparin binding, charge-reversal mutation, R126E, wound healing, diabetes, cell proliferation, metabolic disease, nuclear magnetic resonance spectroscopy
