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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.

Show MeSH
(a) and (c) The obligatory folding nucleus of CAfn2 has moved withinthe hydrophobic core in comparison to (b) and (d) the structurally conservedpositions for TNfn3. The molecules are oriented as in Figure 1. The novel obligatory folding nucleus of CAfn2 isbased on the Φ-values and contact maps between the residues in the hydrophobicnucleus.
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fig6: (a) and (c) The obligatory folding nucleus of CAfn2 has moved withinthe hydrophobic core in comparison to (b) and (d) the structurally conservedpositions for TNfn3. The molecules are oriented as in Figure 1. The novel obligatory folding nucleus of CAfn2 isbased on the Φ-values and contact maps between the residues in the hydrophobicnucleus.

Mentions: Using the same strategy, the Φ-value pattern of CAfn2 was investigatedto identify the putative obligate folding nucleus, a set of residues withsignificant Φ-values that interact such that these interactions aresufficient to establish the topology of the protein. The layer that containsresidues with consistently high Φ-values in the B and E-strands is layer 3(I55 and L22), as in TNfn3. However, for the C and F-strands, the layer withthe highest Φ-values is layer 4 (V38 and V68). Examination of the structureof CAfn2 shows that although residues L22 and I55, and V38 and V68 sit indifferent core layers, these four residues are still able to pack togetherin the centre of the core to form a ring of contacts (Figure 6). Wesuggest that the residues surrounding the obligate nucleus, residues in theC′-strand and more peripheral residues in the B, C E and F-strands, packonto these obligate nucleus residues and, together, form the criticalcontact layer required to stabilise the transition state structuresufficiently to drive folding.


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

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

(a) and (c) The obligatory folding nucleus of CAfn2 has moved withinthe hydrophobic core in comparison to (b) and (d) the structurally conservedpositions for TNfn3. The molecules are oriented as in Figure 1. The novel obligatory folding nucleus of CAfn2 isbased on the Φ-values and contact maps between the residues in the hydrophobicnucleus.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: (a) and (c) The obligatory folding nucleus of CAfn2 has moved withinthe hydrophobic core in comparison to (b) and (d) the structurally conservedpositions for TNfn3. The molecules are oriented as in Figure 1. The novel obligatory folding nucleus of CAfn2 isbased on the Φ-values and contact maps between the residues in the hydrophobicnucleus.
Mentions: Using the same strategy, the Φ-value pattern of CAfn2 was investigatedto identify the putative obligate folding nucleus, a set of residues withsignificant Φ-values that interact such that these interactions aresufficient to establish the topology of the protein. The layer that containsresidues with consistently high Φ-values in the B and E-strands is layer 3(I55 and L22), as in TNfn3. However, for the C and F-strands, the layer withthe highest Φ-values is layer 4 (V38 and V68). Examination of the structureof CAfn2 shows that although residues L22 and I55, and V38 and V68 sit indifferent core layers, these four residues are still able to pack togetherin the centre of the core to form a ring of contacts (Figure 6). Wesuggest that the residues surrounding the obligate nucleus, residues in theC′-strand and more peripheral residues in the B, C E and F-strands, packonto these obligate nucleus residues and, together, form the criticalcontact layer required to stabilise the transition state structuresufficiently to drive folding.

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