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Plasticity within the obligatory folding nucleus of an immunoglobulin-like domain.

Lappalainen I, Hurley MG, Clarke J - J. Mol. Biol. (2007)

Bottom Line: However, there are rare examples where this nucleation pattern is absent.In this study, we have investigated the folding of a novel member of the fnIII superfamily whose nucleus appears to lack one of the four buried hydrophobic residues.We show that the folding mechanism is unaltered, but the folding nucleus has moved within the hydrophobic core.

View Article: PubMed Central - PubMed

Affiliation: University of Cambridge Department of Chemistry, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW, UK.

ABSTRACT
A number of beta-sandwich immunoglobulin-like domains have been shown to fold using a set of structurally equivalent residues that form a folding nucleus deep within the core of the protein. Formation of this nucleus is sufficient to establish the complex Greek key topology of the native state. These nucleating residues are highly conserved within the immunoglobulin superfamily, but are less well conserved in the fibronectin type III (fnIII) superfamily, where the requirement is simply to have four interacting hydrophobic residues. However, there are rare examples where this nucleation pattern is absent. In this study, we have investigated the folding of a novel member of the fnIII superfamily whose nucleus appears to lack one of the four buried hydrophobic residues. We show that the folding mechanism is unaltered, but the folding nucleus has moved within the hydrophobic core.

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The fnIII sequences containing only a single aromatic residue withinthe predicted obligatory folding nucleus. The frequency of the appearance of agiven amino acid in any position is shown on the y-axis.The majority of the sequences have either phenylalanine at the F-strand ortyrosine at the C-strand folding position.
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fig2: The fnIII sequences containing only a single aromatic residue withinthe predicted obligatory folding nucleus. The frequency of the appearance of agiven amino acid in any position is shown on the y-axis.The majority of the sequences have either phenylalanine at the F-strand ortyrosine at the C-strand folding position.

Mentions: Most fnIII domains (65%) have a single aromatic residue in the proposedfolding nucleus. Analysis of the distribution of aromatic residues in thefour obligatory folding nucleus positions shows clearly that aromatic aminoacids are located preferably within the C–F sheet (Figure 2).Furthermore, the type of aromatic residue present is affected by the solventaccessibility of the β-strand: the C-strand position is partlysolvent-accessible, and hence the majority of aromatic residues occurringwithin this strand are tyrosine (thereby allowing hydrogen bonding of thehydroxyl group with solvent molecules). In contrast, the F-strand positionis deep within the core and phenylalanine is almost always the aromaticresidue of choice. Approximately 20% of the sequences have more than onearomatic residue in the folding nucleus, and again these residues are almostexclusively located in the C–F sheet (86% of all such sequences). Thisasymmetry is likely caused by the presence of an adjacent conservedtryptophan in the B-strand that is essential for stability but not involvedin the folding nucleus.16,18 Interestingly, about 15% of the fnIII domains appear tofold without any aromatic residues at the supposed folding positions,suggesting that a large side-chain is not crucial for the formation of theobligatory nucleus.


Plasticity within the obligatory folding nucleus of an immunoglobulin-like domain.

Lappalainen I, Hurley MG, Clarke J - J. Mol. Biol. (2007)

The fnIII sequences containing only a single aromatic residue withinthe predicted obligatory folding nucleus. The frequency of the appearance of agiven amino acid in any position is shown on the y-axis.The majority of the sequences have either phenylalanine at the F-strand ortyrosine at the C-strand folding position.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2291451&req=5

fig2: The fnIII sequences containing only a single aromatic residue withinthe predicted obligatory folding nucleus. The frequency of the appearance of agiven amino acid in any position is shown on the y-axis.The majority of the sequences have either phenylalanine at the F-strand ortyrosine at the C-strand folding position.
Mentions: Most fnIII domains (65%) have a single aromatic residue in the proposedfolding nucleus. Analysis of the distribution of aromatic residues in thefour obligatory folding nucleus positions shows clearly that aromatic aminoacids are located preferably within the C–F sheet (Figure 2).Furthermore, the type of aromatic residue present is affected by the solventaccessibility of the β-strand: the C-strand position is partlysolvent-accessible, and hence the majority of aromatic residues occurringwithin this strand are tyrosine (thereby allowing hydrogen bonding of thehydroxyl group with solvent molecules). In contrast, the F-strand positionis deep within the core and phenylalanine is almost always the aromaticresidue of choice. Approximately 20% of the sequences have more than onearomatic residue in the folding nucleus, and again these residues are almostexclusively located in the C–F sheet (86% of all such sequences). Thisasymmetry is likely caused by the presence of an adjacent conservedtryptophan in the B-strand that is essential for stability but not involvedin the folding nucleus.16,18 Interestingly, about 15% of the fnIII domains appear tofold without any aromatic residues at the supposed folding positions,suggesting that a large side-chain is not crucial for the formation of theobligatory nucleus.

Bottom Line: However, there are rare examples where this nucleation pattern is absent.In this study, we have investigated the folding of a novel member of the fnIII superfamily whose nucleus appears to lack one of the four buried hydrophobic residues.We show that the folding mechanism is unaltered, but the folding nucleus has moved within the hydrophobic core.

View Article: PubMed Central - PubMed

Affiliation: University of Cambridge Department of Chemistry, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW, UK.

ABSTRACT
A number of beta-sandwich immunoglobulin-like domains have been shown to fold using a set of structurally equivalent residues that form a folding nucleus deep within the core of the protein. Formation of this nucleus is sufficient to establish the complex Greek key topology of the native state. These nucleating residues are highly conserved within the immunoglobulin superfamily, but are less well conserved in the fibronectin type III (fnIII) superfamily, where the requirement is simply to have four interacting hydrophobic residues. However, there are rare examples where this nucleation pattern is absent. In this study, we have investigated the folding of a novel member of the fnIII superfamily whose nucleus appears to lack one of the four buried hydrophobic residues. We show that the folding mechanism is unaltered, but the folding nucleus has moved within the hydrophobic core.

Show MeSH