Propagation of Fibrillar Structural Forms in Proteins Stopped by Naturally Occurring Short Polypeptide Chain Fragments

Irena Roterman,Leszek Konieczny,Mateusz Banach

doi:10.3390/ph10040089

Abstract

Amyloids characterized by unbounded growth of fibrillar structures cause many pathological processes. Such unbounded propagation is due to the presence of a propagating hydrophobicity field around the fibril’s main axis, preventing its closure (unlike in globular proteins). Interestingly, similar fragments, commonly referred to as solenoids, are present in many naturally occurring proteins, where their propagation is arrested by suitably located “stopper” fragments. In this work, we analyze the distribution of hydrophobicity in solenoids and in their corresponding “stoppers” from the point of view of the fuzzy oil drop model (called FOD in this paper). This model characterizes the unique linear propagation of local hydrophobicity in the solenoid fragment and allows us to pinpoint “stopper” sequences, where local hydrophobicity quite closely resembles conditions encountered in globular proteins. Consequently, such fragments perform their function by mediating entropically advantageous contact with the water environment. We discuss examples of amyloid-like structures in solenoids, with particular attention to “stop” segments present in properly folded proteins found in living organisms.

Highlights

Protein folding anomalies, in the context of prions [1], cause a range of pathologies, including bovine spongiform encephalopathy [2] as well as Alzheimer’s disease [3]
In order to determine which residues comprise the “stop” signal, we focus on fragments directly adjacent to the terminal beta folds which comprise the solenoid
Such fragments have been subjected to analysis based on the fuzzy oil drop model; we expect that knowledge regarding their structure may be reused to design artificial “stoppers” preventing aggregation of amyloid proteins in misfolding diseases

Summary

Introduction

In the context of prions [1], cause a range of pathologies, including bovine spongiform encephalopathy (commonly known as mad cow disease) [2] as well as Alzheimer’s disease [3]. Depending on the relations between these parameters, the resulting micelle can range from spherical (for a perfectly symmetrical protein) through various elongated globules, all the way to cylindrical solenoids and ribbon-like amyloid fibrils [9]. Further analysis of this broad spectrum of structural forms leads to a set of proteins containing solenoid fragments. Spherical and globular structures tend to exhibit a single centralized hydrophobicity peak, while in elongated forms (cylinders and ribbons) the distribution is linear, with local peaks propagating along the axis of the micelle. The study set comprises proteins which contain solenoid fragments, i.e., structures where the local hydrophobicity profile can propagate linearly, bracketed by “stop” sequences which prevent excessive propagation

Results

Dataset

Fuzzy Oil Drop Model

Hydrophobicity Scale

Identification of “Stop” Sequences

Discussion and Conclusions