Review
Biochemistry & Molecular Biology
Devlina Chakravarty, Joseph W. Schafer, Lauren L. Porter
Summary: Some proteins can change their functions by remodeling their secondary and tertiary structures in response to cellular stimuli. These fold-switching proteins are associated with autoimmune dysfunction, severe acute respiratory syndrome coronavirus-2 infection, and more. This review discusses the features that distinguish fold-switching proteins from single-fold and intrinsically disordered proteins, with the aim of advancing computational prediction and experimental characterization of fold switchers.
Article
Biochemistry & Molecular Biology
Devlina Chakravarty, Lauren L. Porter
Summary: AlphaFold2 revolutionized protein structure prediction, but its predictions tend to be inaccurate for structurally heterogeneous proteins. Analysis of sequence variation showed that fold-switching regions have similar conservation rates to canonical single-fold proteins, while intrinsically disordered regions have lower prediction confidences.
Review
Biochemistry & Molecular Biology
Irina Artsimovitch, Cesar A. Ramirez-Sarmiento
Summary: Metamorphic proteins present unexpected paradigms in protein folding, as their sequences encode two alternative folds that can reversibly interconvert and trigger different cellular responses. This phenomenon may be common among proteins that need to respond to rapidly changing environments. This article summarizes the structural and functional evidence of RfaH as a metamorphic protein, describes the molecular mechanism and refolding pathways of its structural interconversion, and discusses ongoing efforts to identify signatures and general properties of the protein metamorphome.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Multidisciplinary Sciences
Acacia F. Dishman, Robert C. Tyler, Jamie C. Fox, Andrew B. Kleist, Kenneth E. Prehoda, M. Madan Babu, Francis C. Peterson, Brian F. Volkman
Summary: Through ancestral reconstruction and nuclear magnetic resonance, this study investigated the evolution of the metamorphic protein XCL1 and how it switches between two distinct folds. The evolution of XCL1 involved changes in dimer interface, structural constraints, and intramolecular protein contacts, leading to the development of its two different folds. These findings offer insights into how one sequence can evolve to encode multiple structures, with implications for protein design and engineering.
Article
Biochemistry & Molecular Biology
Lauren L. Porter
Summary: Fold-switching proteins can alter their functions by remodeling their secondary structures in response to environmental cues. High-throughput predictive methods have been developed to accurately identify such proteins, offering new insights into disease treatment possibilities.
Article
Biochemistry & Molecular Biology
Lauren L. Porter
Summary: Fold-switching proteins remodel their structures in response to cellular stimuli, challenging the assumption that protein fold space is discrete. Three recent observations support the concept of fluid fold space: interconversion between folds with different secondary structures, fold switching by stepwise mutation, and evolutionary selection of fold switching. These observations highlight the potential of minor amino acid sequence modifications to transform protein structure and expand proteomic diversity through alternative splicing, nucleotide polymorphisms, post-translational modifications, and translation rate modifications.
Article
Multidisciplinary Sciences
Biao Ruan, Yanan He, Yingwei Chen, Eun Jung Choi, Yihong Chen, Dana Motabar, Tsega Solomon, Richard Simmerman, Thomas Kauffman, D. Travis Gallagher, John Orban, Philip N. Bryan
Summary: In order to better understand how protein structure is encoded by amino acid sequence, we created mutational pathways connecting three common folds and analyzed the stability and function of the proteins at high sequence-identity intersections. By embedding the amino acid sequence encoding a smaller fold into a larger fold and designing a new sequence compatible with two sets of native interactions, we generated protein pairs with different folds. Furthermore, the substitution of a single amino acid in the larger folds can switch both their fold and function. These findings shed light on the ambiguity in the protein folding code and demonstrate the possibility of abrupt fold switching in the evolution of new protein structures.
NATURE COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Allen K. Kim, Lauren L. Porter
Summary: The review compares fold-switching proteins with other types of proteins and provides examples of how proteins can change their functions through fold switching. Additionally, it discusses the regulation of biological processes by fold-switching proteins through case studies of RfaH and KaiB. Finally, the review speculates on the future advancements in the field of protein fold switching.
Article
Biochemistry & Molecular Biology
Mihaly Mezei
Summary: The study suggests that fold-switching proteins have weaker foldability on average, but there is almost no difference in the propensity of chameleon sequences between fold switchers and non fold switchers. Interestingly, there are even opposing trends in the amino acid propensities between these two groups.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2021)
Article
Biochemistry & Molecular Biology
Premila P. Samuel Russell, Meredith M. Rickard, Mayank Boob, Martin Gruebele, Taras V. Pogorelov
Summary: This study examines the influence of cellular interactions on the early folding events of a three-helix bundle protein in the cytoplasm. It is found that even fast-folding proteins can get stuck in non-native states in the cell, making them useful models for studying protein-chaperone interactions and early stages of aggregate formation relevant to cellular disease.
Article
Chemistry, Physical
Sridip Parui, Emiliano Brini, Ken A. Dill
Summary: This article introduces a modeling method called limited data (MELD) x MD, which accurately and efficiently calculates the free-energy difference between protein conformations by simulating known stable states A and B without knowing reaction coordinates. Validation experiments suggest that this method can better resolve structures that confuse machine learning methods.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Ning Zhang, Wenyan Guan, Shouqi Cui, Nana Ai
Summary: This study investigates how complex and crowded intracellular environments affect the conformational rearrangement of metamorphic proteins, revealing that crowded agents primarily impact the exchange rate of XCL1 on a timescale of seconds, but have a slight impact on the exchange rate of KaiB on a timescale of hours. NMR spectroscopy is used to quantify the kinetics and thermodynamics of the switch.
COMMUNICATIONS CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Hippolyte Personne, Thierry Paschoud, Sofia Fulgencio, Steïphane Baeriswyl, Thilo Kohler, Christian van Delden, Achim Stocker, Sacha Javor, Jean-Louis Reymond
Summary: Membrane disruptive alpha-helical antimicrobial peptides (AMPs) have potential in addressing multidrug resistance, although most AMPs suffer from toxicity and instability in serum. This study investigated 31 diastereomers of an alpha-helical AMP to assess the effects of introducing D-residues. Three diastereomers with D-residues showed improved antibacterial effects, reduced toxicity, and stability in serum, while another diastereomer displayed lower hemolysis. The relationship between alpha-helicity, antibacterial activity, and hemolysis was complex and highlighted the potential of diastereomers for property optimization.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Immunology
Fangwei Leng, Wenxiang Zhang, Ricardo N. Ramirez, Juliette Leon, Yi Zhong, Lifei Hou, Koichi Yuki, Joris van der Veeken, Alexander Y. Rudensky, Christophe Benoist, Sun Hur
Summary: It has been discovered that FoxP3 can exist in two different dimerization forms, head-to-head dimerization and swap dimerization, with the former being associated with functional specificity and the latter being associated with functional impairment.
Article
Biochemistry & Molecular Biology
Philippe Youkharibache
Summary: The Ig fold has been successful in vertebrate evolution and is present in a significant percentage of human genes. It is not only the elementary structural domain of antibodies and TCRs, but also a core component of 30% of immunologic cell surface receptors, playing a major role in cell-cell interactions.
