Focus on Prions and Amyloids

Featured Review

High-resolution structure of infectious prion protein: the final frontier

Rodrigo Diaz-Espinoza & Claudio Soto

PrPSc, the infective agent for transmissible spongiform encephalopathies, is the misfolded form of the prion protein that can template the conversion of the native form (PrPC). The high-resolution structure of PrPSc remains elusive. This review presents recent progress in the area and existing structural models, in addition to discussing the challenges ahead.

Nature Structural & Molecular Biology 19, 370-377 (2012)


Current Research

The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β1-40 peptide

Priyanka Narayan, Angel Orte, Richard W Clarke, Benedetta Bolognesi, Sharon Hook, Kristina A Ganzinger, Sarah Meehan, Mark R Wilson, Christopher M Dobson & David Klenerman

Genome-wide association studies have established a link between the extracellular chaperone clusterin and susceptibility to Alzheimer's disease. A fluorescence approach is used to reveal that clusterin sequesters Aβ1-40 oligomers and prevents them from undergoing further aggregation.

Nature Structural & Molecular Biology 19, 79-83 (2012)


An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity

Weirui Guo, Yanbo Chen, Xiaohong Zhou, Amar Kar, Payal Ray, Xiaoping Chen, Elizabeth J Rao, Mengxue Yang, Haihong Ye, Li Zhu, Jianghong Liu, Meng Xu, Yanlian Yang, Chen Wang, David Zhang, Eileen H Bigio, Marsel Mesulam, Yan Shen, Qi Xu, Kazuo Fushimi & Jane Y Wu

The TARDBP gene encodes TDP-43, a multifunctional DNA- and RNA-binding protein involved in many cellular processes. Mutations in TARDBP are associated with TDP-43 proteinopathies. In vivo and in vitro studies of mutants and peptides show similarities between TDP-43 and prion proteins, suggesting that TDP-43 derivatives may cause disease by spreading to neighboring neurons.

Nature Structural & Molecular Biology18, 822-830 (2011)


Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange

Vytautas Smirnovas, Gerald S Baron, Danielle K Offerdahl, Gregory J Raymond, Byron Caughey & Witold K Surewicz

Hydrogen-deuterium exchange/mass spec analysis of PrPSc derived from mouse brains reveals that the infectious form of the prion adopts conformations that differ substantially from those previously postulated by various structural models.

Nature Structural & Molecular Biology 18, 504-506 (2011)


Dominant prion mutants induce curing through pathways that promote chaperone-mediated disaggregation

Susanne DiSalvo, Aaron Derdowski, John A Pezza & Tricia R Serio

Yeast Sup35 can misfold and form aggregates to create a prion phenotype, [PSI+]. The mechanisms through which two dominant-negative mutations in Sup35 (Q24R and G58D) cause prion curing are now investigated. The work reveals that the mutations affect the dynamics of aggregates in cells, leading to their resolubilization by the chaperone Hsp104.

Nature Structural & Molecular Biology 18, 486-492 (2011)


Strain conformation, primary structure and the propagation of the yeast prion [PSI+]

Katherine J Verges, Melanie H Smith, Brandon H Toyama & Jonathan S Weissman

[PSI+] is a well-studied prion from budding yeast. Here the dominant-negative effects of mutation G58D are found to depend on the prion conformation. Moreover, the curing effect of G58D on one particular prion conformation is attributed to an impact on the delivery of infectious particles from the mother to the daughter cells.

Nature Structural & Molecular Biology 18, 493-499 (2011)


Critical nucleus size for disease-related polyglutamine aggregation is repeat-length dependent

Karunakar Kar, Murali Jayaraman, Bankanidhi Sahoo, Ravindra Kodali & Ronald Wetzel

The formation of aggregates of polyglutamine (polyQ) sequences is initiated by nucleated growth polymerization. New results show that over a short repeat length range from Q26 to Q23 the size of the nucleus changes from monomeric to dimeric to tetrameric, suggesting aggregation nucleus size has a role in pathogenicity.

Nature Structural & Molecular Biology 18, 328-336 (2011)


β2-microglobulin forms three-dimensional domain-swapped amyloid fibrils with disulfide linkages

Cong Liu, Michael R Sawaya & David Eisenberg

β2-microglobulin can form different forms of amyloid fibrils within joints of dialysis patients. The crystal structures of a β2m domain swapped dimer and of the steric zipper formed by a short peptide indicate how these fibrils might form.

Nature Structural & Molecular Biology 18, 49-55 (2011)


Optical trapping with high forces reveals unexpected behaviors of prion fibrils

Jijun Dong, Carlos E Castro, Mary C Boyce, Matthew J Lang & Susan Lindquist

Amyloid fibrils feature in many human diseases and in epigenetic memory, but understanding their molecular structure has been difficult. Through a combination of optical trapping and fluorescent imaging to examine amyloid fibrils of the yeast prion protein Sup35, the unexpected unfolding of individual subdomains has been detected, suggesting strong noncovalent interactions maintain the fibril even if individual monomers unfold.

Nature Structural & Molecular Biology 17, 1422-1430 (2010)


Solid-state NMR and SAXS studies provide a structural basis for the activation of αB-crystallin oligomers

Stefan Jehle, Ponni Rajagopal, Benjamin Bardiaux, Stefan Markovic, Ronald Kühne, Joseph R Stout, Victoria A Higman, Rachel E Klevit, Barth-Jan van Rossum & Hartmut Oschkinat

Nature Structural & Molecular Biology 17, 1037-1042 (2011)

The structure of the small heat shock protein αB-crystallin, associated with multiple sclerosis and Alzheimer's disease, has eluded biologists for years. Small angle X-ray scattering and solid-state NMR reveal a curved dimer that modulates substrate interactions upon a change in pH.


Structural conversion of neurotoxic amyloid-β1-42 oligomers to fibrils

Mahiuddin Ahmed, Judianne Davis, Darryl Aucoin, Takeshi Sato, Shivani Ahuja, Saburo Aimoto, James I Elliott, William E Van Nostrand & Steven O Smith

Amyloid-β1-42 (Aβ42) peptide aggregates to form oligomers, protofibrils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. Structural and functional analyses show that the conversion of Aβ42 oligomers to fibrils is accompanied by reduced neurotoxicity and involves the formation of parallel, in-register β-sheets that are staggered at an intermolecular contact.

Nature Structural & Molecular Biology 17, 561-567 (2010)


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