The structural paradigm that the sequence of a protein encodes for a unique three-dimensional native fold does not acknowledge the intrinsic plasticity encapsulated in conformational free energy landscapes. Metamorphic proteins are a recently discovered class of biomolecules that illustrate this plasticity by folding into at least two distinct native state structures of comparable stability in the absence of ligands or cofactors to facilitate fold-switching. The expanding list of metamorphic proteins clearly shows that these proteins are not mere aberrations in protein evolution, but may have actually been a consequence of distinctive patterns in selection pressure such as those found in virus–host co-evolution. In this review, we describe the structure–function relationships observed in well-studied metamorphic protein systems, with specific focus on how functional residues are sequestered or exposed in the two folds of the protein. We also discuss the implications of metamorphosis for protein evolution and the efforts that are underway to predict metamorphic systems from sequence properties alone.

蛋白质序列为独特的三维原生折叠编码的结构范式不承认封装在构象自由能景观中的内在可塑性。变质蛋白是最近发现的一类生物分子，它通过在没有配体或辅助因子的情况下折叠成至少两个具有可比稳定性的不同天然状态结构来说明这种可塑性，以促进折叠转换。不断扩大的变质蛋白列表清楚地表明，这些蛋白质不仅仅是蛋白质进化中的畸变，而实际上可能是选择压力的独特模式的结果，例如在病毒-宿主共同进化中发现的那些。在这篇综述中，我们描述了在经过充分研究的变质蛋白系统中观察到的结构-功能关系，特别关注功能性残基如何在蛋白质的两个折叠中被隔离或暴露。我们还讨论了变态对蛋白质进化的影响，以及正在进行的仅从序列特性预测变态系统的努力。