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      Proteinase K resistant cores of prions and amyloids

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          ABSTRACT

          Amyloids and their infectious subset, prions, represent fibrillary aggregates with regular structure. They are formed by proteins that are soluble in their normal state. In amyloid form, all or part of the polypeptide sequence of the protein is resistant to treatment with proteinase K (PK). Amyloids can have structural variants, which can be distinguished by the patterns of their digestion by PK. In this review, we describe and compare studies of the resistant cores of various amyloids from different organisms. These data provide insight into the fine structure of amyloids and their variants as well as raise interesting questions, such as those concerning the differences between amyloids obtained ex vivo and in vitro, as well as the manner in which folding of one region of the amyloid can affect other regions.

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          A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly.

          B Giasson, I Murray, J Trojanowski … (2001)
          Neuronal and oligodendrocytic aggregates of fibrillar alpha-synuclein define several diseases of the nervous system. It is likely that these inclusions impair vital metabolic processes and compromise viability of affected cells. Here, we report that a 12-amino acid stretch ((71)VTGVTAVAQKTV(82)) in the middle of the hydrophobic domain of human alpha-synuclein is necessary and sufficient for its fibrillization based on the following observations: 1) human beta-synuclein is highly homologous to alpha-synuclein but lacks these 12 residues, and it does not assemble into filaments in vitro; 2) the rate of alpha-synuclein polymerization in vitro decreases after the introduction of a single charged amino acid within these 12 residues, and a deletion within this region abrogates assembly; 3) this stretch of 12 amino acids appears to form the core of alpha-synuclein filaments, because it is resistant to proteolytic digestion in alpha-synuclein filaments; and 4) synthetic peptides corresponding to this 12-amino acid stretch self-polymerize to form filaments, and these peptides promote fibrillization of full-length human alpha-synuclein in vitro. Thus, we have identified key sequence elements necessary for the assembly of human alpha-synuclein into filaments, and these elements may be exploited as targets for the design of drugs that inhibit alpha-synuclein fibrillization and might arrest disease progression.
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            Structural insights into a yeast prion illuminate nucleation and strain diversity.

            Rajaraman Krishnan, Susan Lindquist (2005)
            Self-perpetuating changes in the conformations of amyloidogenic proteins play vital roles in normal biology and disease. Despite intense research, the architecture and conformational conversion of amyloids remain poorly understood. Amyloid conformers of Sup35 are the molecular embodiment of the yeast prion known as [PSI], which produces heritable changes in phenotype through self-perpetuating changes in protein folding. Here we determine the nature of Sup35's cooperatively folded amyloid core, and use this information to investigate central questions in prion biology. Specific segments of the amyloid core form intermolecular contacts in a 'Head-to-Head', 'Tail-to-Tail' fashion, but the 'Central Core' is sequestered through intramolecular contacts. The Head acquires productive interactions first, and these nucleate assembly. Variations in the length of the amyloid core and the nature of intermolecular interfaces form the structural basis of distinct prion 'strains', which produce variant phenotypes in vivo. These findings resolve several problems in yeast prion biology and have broad implications for other amyloids.
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              A novel human disease with abnormal prion protein sensitive to protease.

              Claudio Soto, Marcelo Barria, Thomas Wisniewski … (2008)
              To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion. Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and PrP characteristics. Patients presented with behavioral and psychiatric manifestations on average at 62 years, whereas mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern, and the presence of microplaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. After enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly 4 times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the National Prion Disease Pathology Surveillance Center. Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame. The distinct histopathological, PrP immunohistochemical, and physicochemical features, together with the homogeneous genotype, indicate that this is a previously unidentified type of disease involving the PrP, which we designated "protease-sensitive prionopathy" (or PSPr). Protease-sensitive prionopathy is not rare among prion diseases, and it may be even more prevalent than our data indicate because protease-sensitive prionopathy cases are likely also to be classified within the group of non-Alzheimer's dementias.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Prion
                Journal ID (iso-abbrev): Prion
                Journal ID (publisher-id): KPRN
                Journal ID (publisher-id): kprn20
                Title: Prion
                Publisher: Taylor & Francis
                ISSN (Print): 1933-6896
                ISSN (Electronic): 1933-690X
                Publication date Collection: 2020
                Publication date (Electronic): 26 December 2019
                Publication date PMC-release: 26 December 2019
                Volume: 14
                Issue: 1
                Pages: 11-19
                Affiliations
                Research Center of Biotechnology of Russian Academy of Sciences, A.N. Bach Institute of Biochemistry , Moscow, Russia
                Author notes
                CONTACT Vitaly V. Kushnirov vvkushnirov@ 123456gmail.com Research Center of Biotechnology of Russian Academy of Sciences, A.N. Bach Institute of Biochemistry , Leninsky Ave., 33, bldg. 2, Moscow, 119071, Russia
                Author information
                http://orcid.org/0000-0003-0316-0766
                http://orcid.org/0000-0002-0696-923X
                http://orcid.org/0000-0001-7250-4740
                Article
                Publisher ID: 1704612
                DOI: 10.1080/19336896.2019.1704612
                PMC ID: 6959286
                PubMed ID: 31876447
                SO-VID: 3113a1e1-90db-4153-a9c2-65de03a91683
                Copyright © © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 28 November 2019
                Date revision received : 10 December 2019
                Date accepted : 11 December 2019
                Page count
                References: 73, Pages: 9
                Funding
                Funded by: Ministry of Science and Higher Education of the Russian Federation 10.13039/501100003443
                Award ID: none
                Funded by: Grant from the President of the Russian Federation for Young Scientists 10.13039/501100011051
                Award ID: none
                Funded by: Российский Фонд Фундаментальных Исследований (РФФИ) 10.13039/501100002261
                Award ID: 17-04-00032
                This work was supported by the Ministry of Science and Higher Education of the Russian Federation]; Grant from the President of the Russian Federation for Young Scientists; Russian Foundation for Basic Research (RFBR) [17-04-00032].
                Categories
                Subject: Review

                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: amyloid,prion,prion variants,yeast prions,proteinase k,proteinase resistant core
                Data availability:
                ScienceOpen disciplines: Infectious disease & Microbiology
                Keywords: amyloid, prion, prion variants, yeast prions, proteinase k, proteinase resistant core

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