No introductory-level biochemistry textbook is complete without a chapter about how a protein's primary sequence of amino acids determines its fold. Despite much technical progress, however, solving protein structures experimentally remains very laborious and expensive, and knowing the structures of diverse proteins is crucial for both basic research and drug design. Thus, computational prediction of a protein's structure from its amino acid sequence is a challenge of major importance.
Nearly all computational work so far has focused on predicting a single protein structure from the protein's amino acid sequence. Dr. Porter's research challenges the one-sequence-one-structure paradigm. In a recent publication, Loren Looger and she found nearly 100 examples of proteins that can adopt more than one stable fold. This structural heterogeneity allows proteins either to perform more than one function or to be highly regulated in cells. Through the NLM Intramural Research Program, her lab is developing data-driven computational approaches to predict which amino acid sequences can switch folds. She and her lab members validate these predictions experimentally at the National Heart, Lung, and Blood Institute (NHLBI).
This basic research has significant implications for human health. A number of fold-switching proteins are associated with diseases such as cancer, autoimmune disorders, and bacterial and viral infections. Right now, very little is known about how these proteins work. Understanding their mechanisms could lead to development of new therapeutics.
Dr. Lauren Porter is a Distinguished Scholar and Stadtman Tenure-track Investigator with a primary appointment at NLM and a secondary appointment at NHLBI. Prior to coming to the NIH, Dr. Porter spent 7 years studying the biological and biophysical properties of fold-switching proteins, first at the University of Maryland and then at the Howard Hughes Medical Institute, Janelia Research Campus. She is the corresponding author of several recent papers reporting the results of this research. One of them, published in PNAS, was highlighted by two members of Faculty of 1000. For her research on protein fold switching, Dr. Porter has received the Maryland Academy of Science's Outstanding Young Scientist Award (2015) and a National Research Service Award (2014), and she has presented her research at nearly 20 national and international conferences.
- Porter LL, Kim AK, Rimal S, Looger LL, Majumdar A, Mensh BD, Starich MR, Strub MP. Many dissimilar NusG protein domains switch between α-helix and β-sheet folds. Nat Commun. 2022;13(1):3802.
- Chakravarty D, Porter LL. AlphaFold2 fails to predict protein fold switching. Protein Sci. 2022;31(6):e4353.
- Kim AK, Porter LL. Functional and Regulatory Roles of Fold-Switching Proteins. Structure. 2021;29(1):6-14.
- Kim AK, Looger LL, Porter LL. A high-throughput predictive method for sequence-similar fold switchers. Biopolymers. 2021;112(10):e23416.
- Porter LL. Predictable fold switching by the SARS-CoV-2 protein ORF9b. Protein Sci. 2021;30(8):1723-1729.
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This page was last updated on Monday, July 11, 2022