YEARS

-

AUTHORS

Robert Tycko

TITLE

Structural Studies of Prion Fibrils and Other Protein Fibrils

ABSTRACT

Progress in FY2015 was in the following areas: LOW COMPLEXITY SEQUENCES. In collaboration with Prof. Steven McKnight (UT Southwestern Medical Center) and his colleagues, we have performed solid state NMR measurements on fibrils formed by low complexity (LC) sequences of hnRNPA2 and FUS, which are likely to be related to protein aggregates implicated in ALS, FTD. For both hnRNPA2 and FUS LC fibrils, 2D and 3D solid state NMR spectra indicate that only a fraction (20%) of the LC sequence forms the fibril core, with the remaining segments forming flexible loops outside the core. Solid state NMR measurements show that the core is an in-register, parallel cross-beta structure, as in many amyloid fibrils. Chemical shift assignments have been obtained for FUS LC fibrils, showing that approximately 35 residues are contained in the immobilized fibril core. Mass-per-length measurements by dark-field transmission electron microscopy indicate a single FUS LC molecule in each repeat unit along the fibril axis. Additional solid state NMR measurements to develop a full structural model are in progress. MAX1 HYDROGEL FIBRILS. In collaboration with Joel Schneider's group in NCI, we have developed a full structural model for fibrils formed by MAX1, a peptide designed by the Schneider group to form reversible hydrogels comprised of MAX1 fibril meshes. According to solid state NMR data, MAX1 adopts a well-defined beta-hairpin conformation in the fibrils, and beta-hairpins align in parallel with one another within beta-sheet layers. Each fibril contains at least two such layers, stacked in such a way that there is an overall 2-fold symmetry axis parallel the fibril growth axis. This work has now been published in Proc. Natl. Acad. Sci.

FUNDED PUBLICATIONS

  • Experimentally derived structural constraints for amyloid fibrils of wild-type transthyretin.
  • Two prion variants of Sup35p have in-register parallel beta-sheet structures, independent of hydration.
  • Measurement of amyloid fibril mass-per-length by tilted-beam transmission electron microscopy.
  • Repeat domains of melanosome matrix protein Pmel17 orthologs form amyloid fibrils at the acidic melanosomal pH.
  • Amyloids of shuffled prion domains that form prions have a parallel in-register beta-sheet structure.
  • Fiber diffraction data indicate a hollow core for the Alzheimer's aβ 3-fold symmetric fibril.
  • Amyloid of Rnq1p, the basis of the [PIN+] prion, has a parallel in-register beta-sheet structure.
  • Locating folds of the in-register parallel β-sheet of the Sup35p prion domain infectious amyloid.
  • Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels.
  • The α-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel β-sheet structure in PrP fibrils: evidence from solid state nuclear magnetic resonance.
  • Segmental polymorphism in a functional amyloid.
  • Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network.
  • An Achilles' heel in an amyloidogenic protein and its repair: insulin fibrillation and therapeutic design.
  • The functional curli amyloid is not based on in-register parallel beta-sheet structure.
  • How to use: Click on a object to move its position. Double click to open its homepage. Right click to preview its contents.

    Download the RDF metadata as:   json-ld nt turtle xml License info


    29 TRIPLES      15 PREDICATES      29 URIs      7 LITERALS

    Subject Predicate Object
    1 grants:bf156011c278a2adbeb084780c110e2e sg:abstract Progress in FY2015 was in the following areas: LOW COMPLEXITY SEQUENCES. In collaboration with Prof. Steven McKnight (UT Southwestern Medical Center) and his colleagues, we have performed solid state NMR measurements on fibrils formed by low complexity (LC) sequences of hnRNPA2 and FUS, which are likely to be related to protein aggregates implicated in ALS, FTD. For both hnRNPA2 and FUS LC fibrils, 2D and 3D solid state NMR spectra indicate that only a fraction (20%) of the LC sequence forms the fibril core, with the remaining segments forming flexible loops outside the core. Solid state NMR measurements show that the core is an in-register, parallel cross-beta structure, as in many amyloid fibrils. Chemical shift assignments have been obtained for FUS LC fibrils, showing that approximately 35 residues are contained in the immobilized fibril core. Mass-per-length measurements by dark-field transmission electron microscopy indicate a single FUS LC molecule in each repeat unit along the fibril axis. Additional solid state NMR measurements to develop a full structural model are in progress. MAX1 HYDROGEL FIBRILS. In collaboration with Joel Schneider's group in NCI, we have developed a full structural model for fibrils formed by MAX1, a peptide designed by the Schneider group to form reversible hydrogels comprised of MAX1 fibril meshes. According to solid state NMR data, MAX1 adopts a well-defined beta-hairpin conformation in the fibrils, and beta-hairpins align in parallel with one another within beta-sheet layers. Each fibril contains at least two such layers, stacked in such a way that there is an overall 2-fold symmetry axis parallel the fibril growth axis. This work has now been published in Proc. Natl. Acad. Sci.
    2 sg:fundingAmount 2234920.0
    3 sg:fundingCurrency USD
    4 sg:hasContribution contributions:a75789613f333b38dc0d501515c625ef
    5 sg:hasFieldOfResearchCode anzsrc-for:02
    6 anzsrc-for:0299
    7 sg:hasFundedPublication articles:2ce7a2b00f60367654b36c29905c4874
    8 articles:2d41204a7f3be7b7495b20fbcfee6435
    9 articles:2ec08227e1c73091bfb97cacc38297b7
    10 articles:423d471535052157f722dbcffaf01050
    11 articles:490f11fc3cff86e3b3172d659be78b15
    12 articles:4d8393aadbdb327b47956ad2e5fb845b
    13 articles:617117a9f85ac491fab028c6bfa28dfe
    14 articles:65fa7d4989f5c2585daef4cbdf748710
    15 articles:79ff7c96e5e059f3a7c70da80f933a21
    16 articles:84ebb729a1098b539093bb0e7db1b33c
    17 articles:95e0a08ba067cd7adea28055de739b34
    18 articles:ce1553201d8a53000b8041051b1d058e
    19 articles:e54d03303990c7cb0b112bd8d743039d
    20 articles:f07fd08ea0cce496eec5bcc6df9a929d
    21 sg:hasFundingOrganization grid-institutes:grid.419635.c
    22 sg:hasRecipientOrganization grid-institutes:grid.419635.c
    23 sg:language English
    24 sg:license http://scigraph.springernature.com/explorer/license/
    25 sg:scigraphId bf156011c278a2adbeb084780c110e2e
    26 sg:title Structural Studies of Prion Fibrils and Other Protein Fibrils
    27 sg:webpage http://projectreporter.nih.gov/project_info_description.cfm?aid=9148910
    28 rdf:type sg:Grant
    29 rdfs:label Grant: Structural Studies of Prion Fibrils and Other Protein Fibrils
    HOW TO GET THIS DATA PROGRAMMATICALLY:

    JSON-LD is a popular JSON format for linked data.

    curl -H 'Accept: application/ld+json' 'http://scigraph.springernature.com/things/grants/bf156011c278a2adbeb084780c110e2e'

    N-Triples is a line-based linked data format ideal for batch operations .

    curl -H 'Accept: application/n-triples' 'http://scigraph.springernature.com/things/grants/bf156011c278a2adbeb084780c110e2e'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'http://scigraph.springernature.com/things/grants/bf156011c278a2adbeb084780c110e2e'

    RDF/XML is a standard XML format for linked data.

    curl -H 'Accept: application/rdf+xml' 'http://scigraph.springernature.com/things/grants/bf156011c278a2adbeb084780c110e2e'






    Preview window. Press ESC to close (or click here)


    ...