Abstract
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.
Highlights
The single-sequence-structure–function hypothesis is the linchpin that has kept the wheels of structural biology spinning for decades after the first crystal structure of myoglobin was solved by John Kendrew and colleagues in 1958 [1]
Protein dynamics is central for function and has been implicated in malfunction and disease
The conformational heterogeneity observed in proteins is a consequence of the frustration inherent in protein conformational free energy landscapes
Summary
The single-sequence-structure–function hypothesis is the linchpin that has kept the wheels of structural biology spinning for decades after the first crystal structure of myoglobin was solved by John Kendrew and colleagues in 1958 [1] This hypothesis states that the amino acid sequence of a protein codes for a unique native state structure, which performs a distinct function. His dual nature was embodied in his portrayal as a god with two heads facing in opposite directions Given their ability to adopt two or more distinct native state structures, metamorphic proteins are the Janus proteins of structural biology. We outline how the structure is able to inform the function This set of metamorphic proteins is not exhaustive, and other proteins that have been described as metamorphic include selecase [20], MinE [21], CLIC [22] and HIV-1 reverse transcriptase [23]. We point out the synergistic combination of methods that have fostered our current understanding of metamorphic proteins
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