Recent mechanistic insights into conformational interconversion in metamorphic proteins
Buyuan Ma1, Sainan Li2, Zengxin Ma3
1College of Life Sciences, Qingdao Agricultural University, Qingdao, 266109, China; Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, 266101, China.
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Metamorphic proteins defy the classical Anfinsen paradigm by adopting two or more distinct native folds, each associated with unique functions, and they reversibly interconvert under physiological conditions. Recent studies have revealed that these fold-switching events are often regulated by environmental cues such as temperature, pH, and ligand binding, enabling dynamic control over protein function. In this review, we highlight recent mechanistic insights into six well-characterized metamorphic proteins-KaiB, RfaH, XCL1, ORF9b, GXA/GXB and Sa1V90T-and discuss the structural, thermodynamic, and kinetic principles underlying their fold-switching behavior. We further emphasize the emerging roles of advanced NMR techniques in mapping conformational landscapes and quantifying interconversion rates at atomic resolution. Together, these advances provide a comprehensive framework for understanding protein fold-switching as an adaptive mechanism in evolution and regulation.
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