alexa Molecular Basis of Amyloid Polymorphism: Multiple Misfolding Pathways | Open Access Journals
ISSN: 2161-0398
Journal of Physical Chemistry & Biophysics
Like us on:
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on
Medical, Pharma, Engineering, Science, Technology and Business

Molecular Basis of Amyloid Polymorphism: Multiple Misfolding Pathways

Kwang Hun Lim*
Department of Chemistry, East Carolina University, Greenville, NC 27858, USA
Corresponding Author : Kwang Hun Lim
Department of Chemistry
East Carolina University
Greenville, NC 27858, USA
Tel: 1-2523289805
Fax: 1-2523286210
E-mail: [email protected]
Received January 16, 2013; Accepted January 21, 2013; Published January 23, 2013
Citation: Lim KH (2013) Molecular Basis of Amyloid Polymorphism: Multiple Misfolding Pathways. J Phys Chem Biophys 3:e112. doi:10.4172/2161-0398.1000e112
Copyright: © 2013 Lim KH. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Physical Chemistry & Biophysics

Protein misfolding and amyloid formation is implicated in numerous debilitating human diseases such as Alzheimer’s, Parkinson’s and Prion diseases [1]. More than 40 different types of polypeptides including intrinsically disordered as well as natively folded proteins were shown to be associated with amyloid diseases. Prion protein is unique in that the natively folded protein is able to form infectious aggregates with distinct molecular conformations (prion strains), which are proposed to underlie different disease phenotypes [2,3]. A central theme in the prion hypothesis is that the prion strain is encoded in the primary sequence, specifying amyloid conformation and disease phenotype. Mutations of the protein may induce different prion strains and cause distinct disease phenotypes.
Recent studies have suggested that the prion-like mechanism is applicable to other amyloid diseases that also manifest diverse disease phenotypes [2,4]. It is intriguing that natively folded amyloidogenic proteins can form amyloid with distinct morphologies and molecular conformations depending on aggregation conditions, and the structural diversity may be linked to the phenotype variations of amyloid diseases [2]. Elucidation of the multiple amyloid formation processes leading to distinct amyloid conformations is, therefore, of critical importance in identifying therapeutic targets for the fatal human diseases.
Amyloid formation is a complex process involving a series of steps where several intermediate states are populated (Figure 1). Amyloid formation of a natively folded protein can proceed via multiple misfolding and aggregation pathways, which may lead to diverse amyloid conformations [5,6]. The multiple misfolding pathways and polymorphism of amyloid imply that amyloid formation can result from different patterns of inter-residue interactions. The amyloids with distinct molecular conformations (amyloid strains) may have different toxic activities related to the phenotype diversity of amyloid diseases. Understanding the multiple misfolding and amyloid formation pathways is essential to unraveling molecular mechanism of amyloid polymorphism and phenotype diversity.
In this hypothesis, the kinetic folding intermediate of the amyloidogenic proteins has an inherent aggregation propensity, and the pathogenic mutations alter the rugged landscape for the intermediate state and amyloid.
In order to elucidate the complicated amyloid formation pathway, each step of the conformational transitions needs to be examined, requiring structural characterization of the initial conformational transition and the final product, amyloid (Figure 2). Previous biophysical studies showed that a natively folded protein must undergo a local and/or global unfolding transition to intermediate states in the misfolding pathway [1]. The partly unfolded intermediate is also believed to adopt a dynamic conformational ensemble [7]. The conformers present in the conformational ensemble may selfassemble into amyloid with distinct molecular conformations (Figure 1). Pathogenic mutations may facilitate a common misfolding pathway by lowering the energy barrier and/or by stabilizing a common aggregation competent conformer in the ensemble. In this hypothesis, amyloids derived from mutant forms of the protein would have similar amyloid conformations. On the other hand, the mutations may stabilize a different conformer in the aggregation-prone ensemble, leading to distinct amyloid conformations (Figure 1). Comprehensive structural studies of misfolding and amyloid formation for wild-type and various pathogenic mutant forms would be required to test the amyloid strain hypothesis.
The structural studies of the initial transition from the native state to (partly) unfolded intermediate and the end product amyloid (Figure 2) have, however, been challenging due to the millisecond time scale conformational fluctuation of the amyloidogenic intermediate state and the non-crystalline nature of amyloid. Recent advances in biophysical techniques made it possible to investigate the complex problems at atomic resolution. For example, relaxation dispersion solution NMR spectroscopy provided the first atomic-resolution structure of misfolding intermediate state [8]. Molecular dynamics simulations and single-molecule spectroscopy will also play critical roles in exploring mechanistic details of misfolding trajectory for a single-molecule protein [9,10]. In addition, high-resolution structures of insoluble amyloid have begun to be revealed by X-ray crystallography of amyloid-like microcrystals formed from small peptides [11,12] and by solid-state NMR spectroscopy [13-15]. The structural information derived by the multiple biophysical techniques combined with protein engineering will provide unprecedented detailed insights into the misfolding and amyloid formation pathways of the natively folded protein, leading to better understanding of amyloid diversity and amyloid strain hypothesis.
Acknowledgements
Research in Dr. Lim’s lab was supported by a research development grant from the East Carolina University and the Research Corporation.
References

Figures at a glance

Figure Figure
Figure 1 Figure 2
Select your language of interest to view the total content in your interested language
Post your comment

Share This Article

Article Usage

  • Total views: 11601
  • [From(publication date):
    July-2013 - Nov 23, 2017]
  • Breakdown by view type
  • HTML page views : 7831
  • PDF downloads : 3770
 

Post your comment

captcha   Reload  Can't read the image? click here to refresh

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri & Aquaculture Journals

Dr. Krish

[email protected]

1-702-714-7001Extn: 9040

Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001Extn: 9040

Clinical Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

Food & Nutrition Journals

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

General Science

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics & Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Materials Science Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Nursing & Health Care Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

Ann Jose

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001Extn: 9042

 
© 2008- 2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords