Towards understanding secondary structure transitions: phosphorylation and metal coordination in model peptides

Abstract

Secondary structure transitions are important modulators of signal transduction and protein aggregation. Phosphorylation is a well known post-translational modification capable of dramatic alteration of protein secondary structure. Additionally, phosphorylated residues can induce structural changes through metal binding. Data derived from the Protein Data Bank demonstrate that magnesium and manganese are metal ions most favored by phosphate. Due to the complexity of molecular interactions as well as the challenging physicochemical properties of natural systems, simplified peptide models have emerged as a useful tool for investigating the molecular switching phenomenon. In this study using a coiled coil model peptide, we show structural consequences of phosphorylation and subsequent magnesium and manganese ions coordination. In the course of our experiment we obtained a switch cascade starting from a stable helical conformation of the control peptide, continuing through the phosphorylation-induced unfolded structure, and ending with a metal-stabilized alpha-helix (Mg(2+)) or helical fibers (Mn(2+)), each of which could be transferred back to the unfolded form upon EDTA chelation. This study demonstrates how small peptide models can aid in the evaluation and a better understanding of protein secondary structure transitions.

Zinc-Chelating Mechanism of Sea Cucumber (Stichopus japonicus)-Derived Synthetic Peptides

“…Several reports have mentioned that, in the process of chelation between peptides and metal ions, secondary structures of peptides tend to be altered due to the formation of new bonds between metal ions and the peptides. For instance, a naturally occurring cyclic octapeptides could interact with zinc, leading to a concentration-dependent formation of zinc-peptide complex with shift of secondary structures detected by CD spectroscopy [27], including metal-induced conformation of α-helix [28]. However, some divalent or trivalent metal ions, such as Ni 2+ or Cr 3+ , could strongly associate with the carboxyl groups in the linear peptide and prevent the amino and carboxyl groups from forming a cyclic structure [29], which means that the original secondary structures of peptides could be mostly retained after chelation with these metal ions.…”

Inhibition of Amyloid Aggregation by Formation of Helical Assemblies

“…Peptide design: From the series of model peptides developed in recent years [44,46,48,50,51] we chose the peptides VW01 and VW18 ( Figure 1) as representatives of an idealized coiled-coil and amyloid-forming peptide, respectively. The design of both model peptides is based on the well known and highly versatile a-helical coiled-coil folding motif.…”

“…To summarize this previous work, we were able to design model peptides that adopted different conformations and aggregate morphologies depending on the concentration, pH, ionic strength, and the presence of metal ions or other triggers. [46][47][48][49][50] Our earlier success in the rational design of amyloidogenic model peptides encouraged us to investigate strategies to inhibit aggregation. As discussed in detail above, one promising approach is the preclusion of amyloid formation by stabilization of the helical conformation of a target peptide through the formation of stable assemblies.…”

Virtual screening on an α-helix to β-strand switchable region of the FGFR2 extracellular domain revealed positive and negative modulators

“…Conformational transitions between α‐helix and β‐strand may occur due to various environmental changes in temperature, pH, salt concentration, and polarity of the medium . They may be linked to signaling events as residue‐specific phosphorylation, and ligand binding . They may also result from mutations in the protein sequence .…”