A polymetamorphic protein

Stewart, Katie L.; Dodds, Eric D.; Wysocki, Vicki H.; Cordes, Matthew

doi:10.1002/pro.2248

Cited by 7 publications

(27 citation statements)

References 66 publications

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“…In this article, we refer to these variants by the same naming convention used for S-VLV and related Arc surface variants: S indicates the β-strand region of Arc repressor (residues 9-13) and the three other letters denote the amino-acid residues found at the three surface positions of the β-strand, namely residues 9, 11, and 13. 15,20,29 The single and double substitutions do not convert Arc to a higher order oligomer, but instead yield dimers with increased stability against unfolding ( Figure 2 and Table 1). Size exclusion traces show elution volumes similar to those of the wild-type Arc dimer.…”

Section: Sequence Determinants Of Mutationally Induced Oligomerizatmentioning

confidence: 99%

“…The structure of the S‐VLV octamer is unknown, but it seems likely that nonpolar side chains at positions 9, 11, and 13, which form a solvent‐exposed cluster in wild‐type Arc (Figure B), mediate formation of a hydrophobic oligomer interface in a β‐sheet rich structure. Both Arc‐N11L and S‐VLV have higher thermal folding stability than the wild type despite lower conformational specificity …”

Section: Introductionmentioning

confidence: 99%

“…19 The Q9V/N11L/R13V (called S-VLV) variant, which has two additional polar-to-hydrophobic mutations in the same β-sheet, forms an octamer with about half the α-helical content of wild-type Arc. 20 S-VLV also retains the ability to form both dimer structures of Arc-N11L, demonstrating three distinct folded structures. The structure of the S-VLV octamer is unknown, but it seems likely that nonpolar side chains at positions 9, 11, and 13, which form a solvent-exposed cluster in wild-type Arc ( Figure 1B), mediate formation of a hydrophobic oligomer interface in a β-sheet rich structure.…”

mentioning

confidence: 97%

“…Both Arc-N11L and S-VLV have higher thermal folding stability than the wild type despite lower conformational specificity. 15,20 The ability of hydrophobic substitutions to populate additional folded structures almost certainly depends on the specific properties and sequence position of the substituted amino acids, and not solely on the number of substitutions. This is known to be true of fold switching in Arc dimers.…”

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confidence: 99%

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Increased sequence hydrophobicity reduces conformational specificity: A mutational case study of the Arc repressor protein

et al. 2018

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The amino-acid sequences of soluble, globular proteins must have hydrophobic residues to form a stable core, but excess sequence hydrophobicity can lead to loss of native state conformational specificity and aggregation. Previous studies of polar-to-hydrophobic mutations in the β-sheet of the Arc repressor dimer showed that a single substitution at position 11 (N11L) leads to population of an alternate dimeric fold in which the β-sheet is replaced by helix. Two additional hydrophobic mutations at positions 9 and 13 (Q9V and R13V) lead to population of a differently folded octamer along with both dimeric folds. Here we conduct a comprehensive study of the sequence determinants of this progressive loss of fold specificity. We find that the alternate dimer fold specifically results from the N11L substitution and is not promoted by other hydrophobic substitutions in the β-sheet. We also find that three highly hydrophobic substitutions at positions 9, 11 and 13 are necessary and sufficient for oligomer formation, but the oligomer size depends on the identity of the hydrophobic residue in question. The hydrophobic substitutions increase thermal stability, illustrating how increased hydrophobicity can increase folding stability even as it degrades conformational specificity. The oligomeric variants are predicted to be aggregation-prone but may be hindered from doing so by proline residues that flank the β-sheet region. Loss of conformational specificity due to increased hydrophobicity can manifest itself at any level of structure, depending upon the specific mutations and the context in which they occur.

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Section: Sequence Determinants Of Mutationally Induced Oligomerizatmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 97%

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Increased sequence hydrophobicity reduces conformational specificity: A mutational case study of the Arc repressor protein

et al. 2018

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“…For example, DNA binding protein Arc repressor is predominantly monomeric and unfolded at low concentrations, while mostly dimeric at high concentrations in 10 mM KH 2 PO4/K 2 HPO4 and 100 mM KCl with pH = 7.3. 40 Higher and/or different oligomers are not found unless the structure is altered chemically. 41 There are many factors can determine the number of oligomers and/ or the number of subunits/protomer residues in an oligomer.…”

Section: Protein Oligomers Without Covalent Bondsmentioning

confidence: 99%

A review on protein oligomerization process

Liu

2015

Int. J. Precis. Eng. Manuf.

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Enzymes or proteins are commonly present in oligomeric forms for active biological functions. The formation of protein oligomers, either in nature or by artificial means, can take place via covalent bonding or through weak-bond-network associations. Disulfide bonds are more common in forming covalent protein oligomers. Covalent bound protein oligomers usually have additional elements introduced, while proteins associated through weak-bond-networks usually do not involve any additional bound chemical groups. Proteins are commonly present in stable forms or folds. Oligomerization can occur when stable proteins unfold, creating exposed interfaces for association interactions. One well-known process of weak-bond-network oligomerization is domain swapping (DS). Separating the two touching/interacting domains creates opportunities for similar interactions with different protein molecules, leading to oligomerization. Both disulfide bonding and DS oligomerization can be dynamic (or reversible) at least at low Degree of Polymerizations (DPs). The dynamic nature of the protein oligomerization is important for bioactivity control. The morpheein model and the polymorph model are thus important in quantifying enzyme catalyzed biotransformations. Disulfide bonding and DS can act together to form supramolecules. The formation of supramolecules, such as amyloids, in nature can be benign or harmful. Industrial applications of protein oligomerization exploit the special functions /properties of the resultant supramolecules, such as multiple biofunctions, niche structure, etc..

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Multistep mutational transformation of a protein fold through structural intermediates

et al. 2018

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New protein folds may evolve from existing folds through metamorphic evolution involving a dramatic switch in structure. To mimic pathways by which amino acid sequence changes could induce a change in fold, we designed two folded hybrids of Xfaso 1 and Pfl 6, a pair of homologous Cro protein sequences with ~40% identity but different folds (all-α vs. α + β, respectively). Each hybrid, XPH1 or XPH2, is 85% identical in sequence to its parent, Xfaso 1 or Pfl 6, respectively; 55% identical to its noncognate parent; and ~70% identical to the other hybrid. XPH1 and XPH2 also feature a designed hybrid chameleon sequence corresponding to the C-terminal region, which switched from α-helical to β-sheet structure during Cro evolution. We report solution nuclear magnetic resonance (NMR) structures of XPH1 and XPH2 at 0.3 Å and 0.5 Å backbone root mean square deviation (RMSD), respectively. XPH1 retains a global fold generally similar to Xfaso 1, and XPH2 retains a fold similar to Pfl 6, as measured by TM-align scores (~0.7), DALI Z-scores (7-9), and backbone RMSD (2-3 Å RMSD for the most ordered regions). However, these scores also indicate significant deviations in structure. Most notably, XPH1 and XPH2 have different, and intermediate, secondary structure content relative to Xfaso 1 and Pfl 6. The multistep progression in sequence, from Xfaso 1 to XPH1 to XPH2 to Pfl 6, thus involves both abrupt and gradual changes in folding pattern. The plasticity of some protein folds may allow for "polymetamorphic" evolution through intermediate structures.

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A polymetamorphic protein

Cited by 7 publications

References 66 publications

Increased sequence hydrophobicity reduces conformational specificity: A mutational case study of the Arc repressor protein

Increased sequence hydrophobicity reduces conformational specificity: A mutational case study of the Arc repressor protein

A review on protein oligomerization process

Multistep mutational transformation of a protein fold through structural intermediates

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