Abstract
Conformational change plays an important role in the life of all proteins, starting from when they fold, through their function and often their fate. For an increasing number of proteins inappropriate conformational change leads to a chain of events, which culminate in the deposition of proteinacious aggregates and disease. In this review we consider the current literature on a number of proteins which form part of the Conformational Disease family. We describe here two types of aggregate that can be formed, Type I aggregates are typified by the Serpin superfamily and consist of non-fibrillar polymeric species. Type II aggregates are of the classical fibrillar form formed by a diverse range of proteins. Through biochemical and biophysical analyis of the aggregation reaction of members of these two classes we show that they form these aggregates through highly similar pathways. Essentially, the whole process can be summed up in two key stages. Firstly, the existence of conditions which increase the conformational flexibility of the protein, enabling it to adopt a partially folded state. Secondly, the propensity of this intermediate conformer to form intermolecular linkages leads to multimeric forms, a step often mediated via hydrophobic or β-strand interactions. Our understanding of these structural changes has facilitated the rationale design of specific aggregation inhibitors. We will discuss the successes and pitfalls of such approaches to demonstrate how similar approaches may be applied to any misfolding protein.
Keywords: conformational disease, protein misfolding, serpin, polymerization, drug design
Current Medicinal Chemistry
Title: Promiscuous Beta-Strand Interactions and the Conformational Diseases
Volume: 11 Issue: 4
Author(s): Michelle K.M. Chow, David A. Lomas and Stephen P. Bottomley
Affiliation:
Keywords: conformational disease, protein misfolding, serpin, polymerization, drug design
Abstract: Conformational change plays an important role in the life of all proteins, starting from when they fold, through their function and often their fate. For an increasing number of proteins inappropriate conformational change leads to a chain of events, which culminate in the deposition of proteinacious aggregates and disease. In this review we consider the current literature on a number of proteins which form part of the Conformational Disease family. We describe here two types of aggregate that can be formed, Type I aggregates are typified by the Serpin superfamily and consist of non-fibrillar polymeric species. Type II aggregates are of the classical fibrillar form formed by a diverse range of proteins. Through biochemical and biophysical analyis of the aggregation reaction of members of these two classes we show that they form these aggregates through highly similar pathways. Essentially, the whole process can be summed up in two key stages. Firstly, the existence of conditions which increase the conformational flexibility of the protein, enabling it to adopt a partially folded state. Secondly, the propensity of this intermediate conformer to form intermolecular linkages leads to multimeric forms, a step often mediated via hydrophobic or β-strand interactions. Our understanding of these structural changes has facilitated the rationale design of specific aggregation inhibitors. We will discuss the successes and pitfalls of such approaches to demonstrate how similar approaches may be applied to any misfolding protein.
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Cite this article as:
Chow K.M. Michelle, Lomas A. David and Bottomley P. Stephen, Promiscuous Beta-Strand Interactions and the Conformational Diseases, Current Medicinal Chemistry 2004; 11 (4) . https://dx.doi.org/10.2174/0929867043455936
DOI https://dx.doi.org/10.2174/0929867043455936 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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