Functional Amyloids As Natural Storage of Peptide Hormones in Pituitary Secretory Granules

Laboratory of Physical Chemistry, Eidgenössische Technische Hochschule (ETH) Zürich, Wolfgang-Paulistrasse 10, CH-8093 Zürich, Switzerland.
Science (Impact Factor: 33.61). 07/2009; 325(5938):328-32. DOI: 10.1126/science.1173155
Source: PubMed


Amyloids are highly organized cross-beta-sheet-rich protein or peptide aggregates that are associated with pathological conditions including Alzheimer's disease and type II diabetes. However, amyloids may also have a normal biological function, as demonstrated by fungal prions, which are involved in prion replication, and the amyloid protein Pmel17, which is involved in mammalian skin pigmentation. We found that peptide and protein hormones in secretory granules of the endocrine system are stored in an amyloid-like cross-beta-sheet-rich conformation. Thus, functional amyloids in the pituitary and other organs can contribute to normal cell and tissue physiology.

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Available from: Michael R Sawaya, Jun 23, 2014
    • "Since many amyloids are related to disease, the only unwanted targets would be the functional amyloids where the amyloid structure is related to the normal function of the protein. Besides providing a broad spectrum of therapeutic activity, antibodies that recognize generic epitopes have proven to be useful in discovering previously unknown associations between amyloid accumulation and several diseases, such as idiopathic cardiomyopathy[27], preeclampsia[28], andatrialfibrillation[29],andinidentifyingnativeamy- loids[30]. These data further reinforce the idea that recognition of a linear peptide segment is not a reliable indicator of sequence specificity. "
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    ABSTRACT: Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-β (Aβ) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available Aβ antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18-23 of the Aβ sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from α-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not recognize α-synuclein or IAPP monomer. 4G8 also stains fibrillar α-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-α-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes Aβ fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to α-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution.
    No preview · Article · Dec 2015 · Journal of Alzheimer's disease: JAD
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    • "of biological processes, as diverse as biofilm formation, development of aerial structures, regulation of melanin synthesis, hormone production, epigenetic control of polyamines, and information transfer (Fowler et al., 2007; Maji et al., 2009; Maury, 2009b). In the case of prions, several properties, including transmissibility and species specificity seem to be dependent on the amyloid conformation (Jones and Surewicz, 2005; Toyama and Weissman, 2011; Frederick et al., 2014; Wickner et al., 2014). "
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    ABSTRACT: The question of the origin of life on Earth can largely be reduced to the question of what was the first molecular replicator system that was able to replicate and evolve under the presumably very harsh conditions on the early Earth. It is unlikely that a functional RNA could have existed under such conditions and it is generally assumed that some other kind of information system preceded the RNA world. Here, I present an informational molecular system that is stable, self-replicative, environmentally responsive, and evolvable under conditions characterized by high temperatures, ultraviolet and cosmic radiation. This postulated pregenetic system is based on the amyloid fold, a functionally unique polypeptide fold characterized by a cross beta-sheet structure in which the beta strands are arranged perpendicular to the fiber axis. Beside an extraordinary structural robustness, the amyloid fold posses a unique ability to transmit information by a three-dimensional templating mechanism. In amyloidogenesis short peptide monomers are added one by one to the growing end of the fiber. From the same monomeric subunits several structural variants of amyloid may be formed. Then, in a self-replicative mode, a specific amyloid conformer can act as a template and confer its spatially encoded information to daughter molecular entities in a repetitive way. In this process, the specific conformational information, the spatially changed organization, is transmitted; the coding element is the steric zipper structure, and recognition occurs by amino acid side chain complementarity. The amyloid information system fulfills several basic requirements of a primordial evolvable replicator system: (i) it is stable under the presumed primitive Earth conditions, (ii) the monomeric building blocks of the informational polymer can be formed from available prebiotic compounds, (iii) the system is self-assembling and self-replicative and (iv) it is adaptive to changes in the environment and evolvable. Copyright © 2015. Published by Elsevier Ltd.
    Preview · Article · Jul 2015 · Journal of Theoretical Biology
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    • "To probe the amyloidogenicity of the fibril networks, CR and ThT binding studies were performed. Both CR and ThT are known to bind the amyloid form of the protein/peptide aggregates and not to their monomeric counterparts , and were hence used for amyloid detection in vitro and in vivo [36]. ThT generally exhibited an elevated fluorescence signal at 480 nm when bound to amyloid fibrils upon excitation at 450 nm [67]. "
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    ABSTRACT: Amyloids are highly ordered protein/peptide aggregates associated with human diseases as well as various native biological functions. Given the diverse range of physiochemical properties of amyloids, we hypothesized that higher order amyloid self-assembly could be used for fabricating novel hydrogels for biomaterial applications. For proof of concept, we designed a series of peptides based on the high aggregation prone C-terminus of Aβ42, which is associated with Alzheimer's disease. These Fmoc protected peptides self assemble to β sheet rich nanofibrils, forming hydrogels that are thermoreversible, non-toxic and thixotropic. Mechanistic studies indicate that while hydrophobic, π-π interactions and hydrogen bonding drive amyloid network formation to form supramolecular gel structure, the exposed hydrophobic surface of amyloid fibrils may render thixotropicity to these gels. We have demonstrated the utility of these hydrogels in supporting cell attachment and spreading across a diverse range of cell types. Finally, by tuning the stiffness of these gels through modulation of peptide concentration and salt concentration these hydrogels could be used as scaffolds that can drive differentiation of mesenchymal stem cells. Taken together, our results indicate that small size, ease of custom synthesis, thixotropic nature makes these amyloid-based hydrogels ideally suited for biomaterial/nanotechnology applications. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Biomaterials
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