Abstract
Multiple crystal structures of the homo-trimeric protein disulphide isomerase PmScsC reveal that the peptide which links the trimerization stalk and catalytic domain can adopt helical, β-strand and loop conformations. This region has been called a ‘shape-shifter’ peptide. Characterisation of this peptide using NMR experiments and MD simulations has shown that it is essentially disordered in solution. Analysis of the PmScsC crystal structures identifies the role of intermolecular contacts, within an assembly of protein molecules, in stabilising the different linker peptide conformations. These context-dependent conformational properties may be important functionally, allowing for the binding and disulphide shuffling of a variety of protein substrates to PmScsC. They also have a relevance for our understanding of protein aggregation and misfolding showing how intermolecular quaternary interactions can lead to β-sheet formation by a sequence that in other contexts adopts a helical structure. This ‘shape-shifting’ peptide region within PmScsC is reminiscent of one-to-many molecular recognition features (MoRFs) found in intrinsically disordered proteins which are able to adopt different conformations when they fold upon binding to their protein partners.
Highlights
Chameleon sequences, amino acid sequences that adopt different secondary structure conformations in different protein structures, are currently attracting considerable interest [1]
The linker peptide in PmScsC was initially identified as a shape-shifting motif which had potential for plug-and-play applications in protein engineering [11]
The studies of this peptide sequence alone in solution reported here show that it is essentially disordered and the different conformations it adopts in crystal structures of PmScsC are a consequence of different intermolecular hydrogen bonding patterns and crystal contacts formed under a variety of crystallization conditions which differ in pH and ionic strength [11]
Summary
Amino acid sequences that adopt different secondary structure conformations in different protein structures, are currently attracting considerable interest [1]. Biomolecules 2021, 11, 642 trimerization stalk and catalytic domains are essentially unchanged between these three forms but the linker peptide adopts a helical, strand or loop conformation resulting in significant changes in the quaternary structure of the trimer. The transitional crystal structure contains monomers adopting both the compact and extended conformations along with an intermediate conformation in which the linker forms a short β-strand hydrogen bonding to the catalytic domain positioned above the trimerization stalk (Figure 1c). In panel d the linker peptide sequence in molecule A is shown in blue with Lys 38, Glu 42 and Gln 46 highlighted These three residues make hydrogen bonds to Glu 182, Arg 185 and Lys 186 in molecule D which are shown in orange.
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