Evolution of fold switching in a metamorphic protein

Dishman, Acacia F.; Tyler, Robert C.; Fox, Jamie; Kleist, Andrew B.; Prehoda, Kenneth E.; Babu, M. Madan; Peterson, Francis C.; Volkman, Brian F.

doi:10.1126/science.abd8700

Cited by 67 publications

(77 citation statements)

References 56 publications

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“…6 Human lymphotactin (a.k.a. XCL1) iso-energetically populates two β-sheet conformations with completely different hydrogen bonding patterns 7,8 and is associated with autoimmune disorders. 9 Furthermore, human Chloride Intracellular Channel 1 (CLIC1) remodels its secondary structure and changes its function from a glutathione reductase 10 to a chloride channel 11 that balances intracellular chloride levels when cells undergo oxidative stress due to cancer 12 or Alzheimer's.…”

Section: Introductionmentioning

confidence: 99%

Predictable fold switching by theSARS‐CoV‐2 proteinORF9b

Porter

2021

Protein Science

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Extant fold‐switching proteins remodel their secondary structures and change their functions in response to environmental stimuli. These shapeshifting proteins regulate biological processes and are associated with a number of diseases, including tuberculosis, cancer, Alzheimer's, and autoimmune disorders. Thus, predictive methods are needed to identify more fold‐switching proteins, especially since all naturally occurring instances have been discovered by chance. In response to this need, two high‐throughput predictive methods have recently been developed. Here we test them on ORF9b, a newly discovered fold switcher and potential therapeutic target from the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2). Promisingly, both methods correctly indicate that ORF9b switches folds. We then tested the same two methods on ORF9b1, the ORF9b homolog from SARS‐CoV‐1. Again, both methods predict that ORF9b1 switches folds, a finding consistent with experimental binding studies. Together, these results (a) demonstrate that protein fold switching can be predicted using high‐throughput computational approaches and (b) suggest that fold switching might be a general characteristic of ORF9b homologs.

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Section: Introductionmentioning

confidence: 99%

Predictable fold switching by theSARS‐CoV‐2 proteinORF9b

Porter

2021

Protein Science

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“…One counterexample is the intrinsic disorder found in a significant number of functional proteins and protein regions. These intrinsically disordered regions do not adopt a stable three-dimensional structure, instead existing as conformational ensembles of states that may include pre-formed structural nuclei (Dyson, 2016). Other counterexamples are provided by proteins which interconvert among multiple folded states, ranging from a "fragile fold", in which substitution of a few amino acids -even one -results in the domain co-existing in two states Ha and Loh, 2012) to the general concept X.…”

Section: Introductionmentioning

confidence: 99%

“…In metamorphic proteins, which can be considered an extreme case of a fragile fold, an even greater number of hydrogen bonds differ between the two folds as seen in lymphotactin (which alternates between a conventional chemokine fold and a dimeric β sandwich; Kuloglu et al, 2002;Tuinstra et al, 2008). These studies suggest that protein folds may hide unforeseen flexibility or fragility which can be trivially accessed by small changes in sequence or environmental conditions, facilitating the evolution of new folds and protein domains (Yadid et al, 2010;Tuinstra et al, 2008;Alexander et al, 2009;Dishman et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Fragile protein folds: sequence and environmental factors affecting the equilibrium of two interconverting, stably folded protein conformations

Dikiy

Evans³

et al. 2021

Magn. Reson.

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Abstract. Recent research on fold-switching metamorphic proteins has revealed some notable exceptions to Anfinsen's hypothesis of protein folding. We have previously described how a single point mutation can enable a well-folded protein domain, one of the two PAS (Per-ARNT-Sim) domains of the human ARNT (aryl hydrocarbon receptor nuclear translocator) protein, to interconvert between two conformers related by a slip of an internal β strand. Using this protein as a test case, we advance the concept of a “fragile fold”, a protein fold that can reversibly rearrange into another fold that differs by a substantial number of hydrogen bonds, entailing reorganization of single secondary structure elements to more drastic changes seen in metamorphic proteins. Here we use a battery of biophysical tests to examine several factors affecting the equilibrium between the two conformations of the switching ARNT PAS-B Y456T protein. Of note is that we find that factors which impact the HI loop preceding the shifted Iβ strand affect both the equilibrium levels of the two conformers and the denatured state which links them in the interconversion process. Finally, we describe small molecules that selectively bind to and stabilize the wild-type conformation of ARNT PAS-B. These studies form a toolkit for studying fragile protein folds and could enable ways to modulate the biological functions of such fragile folds, both in natural and engineered proteins.

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“…However, in recent decades, proteins have been discovered that defy this norm, folding into multiple different structures and reversibly interconverting between them. Recent work has shown that these proteins, called metamorphic proteins, may be more common than initially expected [ 8 , 9 ]. Interest in the biological relevance of metamorphic protein folding is growing, and efforts to understand and harness protein metamorphosis for therapeutic benefit are beginning to mount [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1

Dishman

Volkman

et al. 2021

Pathogens

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Candida species cause serious infections requiring prolonged and sometimes toxic therapy. Antimicrobial proteins, such as chemokines, hold great interest as potential additions to the small number of available antifungal drugs. Metamorphic proteins reversibly switch between multiple different folded structures. XCL1 is a metamorphic, antimicrobial chemokine that interconverts between the conserved chemokine fold (an α–β monomer) and an alternate fold (an all-β dimer). Previous work has shown that human XCL1 kills C. albicans but has not assessed whether one or both XCL1 folds perform this activity. Here, we use structurally locked engineered XCL1 variants and Candida killing assays, adenylate kinase release assays, and propidium iodide uptake assays to demonstrate that both XCL1 folds kill Candida, but they do so via different mechanisms. Our results suggest that the alternate fold kills via membrane disruption, consistent with previous work, and the chemokine fold does not. XCL1 fold-switching thus provides a mechanism to regulate the XCL1 mode of antifungal killing, which could protect surrounding tissue from damage associated with fungal membrane disruption and could allow XCL1 to overcome candidal resistance by switching folds. This work provides inspiration for the future design of switchable, multifunctional antifungal therapeutics.

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Evolution of fold switching in a metamorphic protein

Cited by 67 publications

References 56 publications

Predictable fold switching by theSARS‐CoV‐2 proteinORF9b

Predictable fold switching by theSARS‐CoV‐2 proteinORF9b

Fragile protein folds: sequence and environmental factors affecting the equilibrium of two interconverting, stably folded protein conformations

Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1

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