Evolution of Fold Switching in a Metamorphic Protein

Overview

Journal Science

Specialty Science

Date 2021 Jan 1

PMID 33384377

Citations 39

Authors

Acacia F Dishman

Robert C Tyler

Jamie C Fox

Andrew B Kleist

Kenneth E Prehoda

M Madan Babu

Francis C Peterson

Brian F Volkman

Affiliations

Soon will be listed here.

Abstract

Metamorphic proteins switch between different folds, defying the protein folding paradigm. It is unclear how fold switching arises during evolution. With ancestral reconstruction and nuclear magnetic resonance, we studied the evolution of the metamorphic human protein XCL1, which has two distinct folds with different functions, making it an unusual member of the chemokine family, whose members generally adopt one conserved fold. XCL1 evolved from an ancestor with the chemokine fold. Evolution of a dimer interface, changes in structural constraints and molecular strain, and alteration of intramolecular protein contacts drove the evolution of metamorphosis. Then, XCL1 likely evolved to preferentially populate the noncanonical fold before reaching its modern-day near-equal population of folds. These discoveries illuminate how one sequence has evolved to encode multiple structures, revealing principles for protein design and engineering.

Citing Articles

Sequence clustering confounds AlphaFold2.

Schafer J, Lee M, Chakravarty D, Thole J, Chen E, Porter L Nature. 2025; 638(8051):E8-E12.

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From duplication to fusion: Expanding Dayhoff's model of protein evolution.

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The multifaceted role of XCL1 in health and disease.

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AlphaFold2's training set powers its predictions of fold-switched conformations.

Schafer J, Porter L bioRxiv. 2025; .

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Proteins with alternative folds reveal blind spots in AlphaFold-based protein structure prediction.

Chakravarty D, Lee M, Porter L ArXiv. 2025; .

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