Peptide Aggregation

Peptides and proteins are able to adopt more than one thermodynamically stable conformation, a property associated with many neurodegenerative conditions, such as Alzheimer’s, Huntington’s, and Creutzfeldt-Jakob disease. In these cases, the changes in protein secondary and tertiary structure are the cause of so-called plaque formation. When deposited in nerve tissues, these insoluble protein aggregates can cause often devastating symptoms of dementia. In spite of having been the focus of numerous scientific studies, the formation of fibrils from monomeric and oligomeric peptide building blocks is not yet understood. By means of the above-described peptide model systems, our lab has studied the role of electrostatic interactions, metal ions, and post-translational modifications in aggregation processes at the molecular level (Pagel, Curr. Opin., 2008; Falenski, Chem. Eur. J., 2010). Our current projects in this area are described below. 

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Although amyloid-forming proteins have diverse structures and sequences, all undergo a conformational change to form amyloid aggregates that have a characteristic cross-β-structure. In spite of the fact that the mechanistic details of this process are poorly understood, numerous strategies for the development of inhibitors of amyloid formation have been proposed. In most cases, chemically diverse compounds inhibit by binding to an elongated form of the protein in a β-strand conformation. However, this approach could favor the formation of prefibrillar oligomeric species, which are thought to be toxic.


Figure 1: Helical inihibitor approach to disrupting amyloid fibril formation

We have utilized an alternative approach, in which a helical coiled-coil-based inhibitor peptide engages a coiled-coil-based amyloid-forming model peptide in a stable coiled-coil arrangement, thereby precluding rearrangement into a β-sheet conformation and the subsequent formation of amyloid-like fibrils. Moreover, we have shown that the helix-forming peptide is able to disassemble mature amyloid-like fibrils (Brandenburg, Chem. Eur. J., 2011). 

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Phosphorylation is one of the most important postranslational protein modifications in nature. Investigating the impact of the electronegative phosphate group on the conformation of peptides is of great interest for the elucidation of many pathologic events, such as tauopathies. Depending upon the location of this covalent modification, and the neighboring functional groups in the peptide, enzymatic phosphorylation can either stabilize or destabilize specific conformational states (Broncel, Chem. Eur. J., 2010).

Figure 2. Pathway of amyloid formation and inhibition by phosphorylation.

We have shown that incorporation of phosphoserines into a 26-residue, amyloid-forming model peptide precludes amyloid formation, and that enzymatic dephosphorylation of these peptides with phosphatase lambda (λ-APPase) can induce a conformational switch from a coiled coil structure to amyloids (Broncel, Chem. Eur. J., 2010; Broncel, Chem. Commun. 2010). Furthermore, we developed a peptide system that enables detailed amyloid-aggregation inhibition studies using cAMP dependent Proteinkinase A (PKA) (Figure 2). Further systematic studies of this kind will contribute significantly to our understanding of how phosphorylation influences pathways leading to peptide aggregation, and which structural interactions affect the conformation of a peptide during this process. 

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