Author: Patrick

Our new review article discussing the concept of dynamics-based spectral editing (DYSE) in ssNMR is now available online in the journal Methods. In it, we describe how the dynamics-sensitive pulse sequences enable the filtering out (or spectral editing) of signals based on their differences in dynamics. Applications by ourselves and many other groups are discussed. Notably, these applications range across a huge swatch of different sample types, going from designer peptide nano materials to whole tissues and even living organisms.

Citation:

• Hidden motions and motion-induced invisibility: dynamics-based spectral editing in solid-state NMR. Matlahov, I., Van der Wel, P.C.A. Methods, in press [URL]

Our new paper discussing the role of modern solid-state NMR in integrated structural biology is now published in Emerging Topics in Life Sciences. It provides a review of a selection of recent solid-state NMR studies from (mostly) the last decade. Not only does it give a review of notable 3D structures obtained by solid-state NMR, but it also examines contributions going beyond static protein structures. This includes the characterization of biologically relevant dynamics, and the pinpointing of crucial intermolecular interactions.

Reference:

• Patrick C.A. van der Wel (2018) “New applications of solid-state NMR in structural biology.” Emerging Topics in Life Sciences, Vol. 2, pp. 57–67

Access:

• DOI: 10.1042/ETLS20170088
• Request reprints by email: vanderwel@pitt.edu.
• Open Access PDF for download: OA PDF

Congratulations to collaborator Giorgio Cavigiolio, his group at CHORI (Children’s Hospital Oakland Research Institute), and Jennifer Boatz on the publication of our new collaborative paper. It reports functional and structural studies of the effect of oxidation on apolipoprotein A-I (ApoA1), using a variety of experiments and assays – including solid-state NMR. Oxidation of the protein causes it to become more monomeric and also less stably folded. As a consequence it becomes prone to aggregation into amyloid-like fibrils. Interestingly, these oxidized aggregates are able to subvert non-oxidized protein into an amyloidogenic (i.e. aggregation-prone) state. Another interesting aspect of these aggregated proteins is that they may feature a typical amyloid core structure composed of β-sheets, but that large parts of the protein stay outside this core structure. These latter “flanking”domains retain much of their native α-helical fold, somewhat reminiscent of our prior findings in the Huntington’s disease protein. We hypothesize that these non-amyloid domains may mediate interactions not only within the fibrils but also between fibrils and still-soluble native proteins. The paper also discusses the potential role of these molecular processes in atherosclerosis.

The paper:
Andrzej Witkowski, Gary K. L. Chan, Jennifer C. Boatz, Nancy J. Li, Ayuka P. Inoue, Jaclyn C. Wong, Patrick C. A. van der Wel, and Giorgio Cavigiolio (2018) “Methionine oxidized apolipoprotein A-I at the crossroads of HDL biogenesis and amyloid formation” FASEB Journal, in press. Online at the journal, and also on PubMed.

Congratulations to our collaborators for the new collaborative paper on the characteristic twisting of amyloid fibril filaments, which has just appeared online as accepted for publication in the Journal of Physical Chemistry B. The paper, titled “Energetics Underlying Twist Polymorphisms in Amyloid Fibrils“, describes molecular dynamics simulations of the twisting of amyloid-like structures of the GNNQQNY peptide fragment from the yeast prion protein Sup35p. This particular peptide has developed into an essential model system for studies of the structure and formation of amyloid fibrils, and (for instance) how they differ from crystalline assemblies formed by these and other polypeptides [1-3].

The full citation is:
Energetics Underlying Twist Polymorphisms in Amyloid Fibrils.
Periole, X., Huber, T., Bonito-Oliva, A., Aberg, K.C., Van der Wel, P.C.A., Sakmar, T.P., & Marrink, S.J. (2018) J. Phys. Chem. B 122 (3), pp 1081–1091

Accessible online at the journal.

Related references:

[1] Nelson et al. (2005)  Nature 435(7043): 773-778
[2] Van der Wel et al. (2007)  J Am Chem Soc 129(16): 5117-5130
[3] Van der Wel et al. (2010)  Biochemistry 49(44): 9457-9469

Our new review article summarizing recent findings on protein aggregation enabled by solid-state NMR is now online. This “Trends” article will appear in the journal Solid-state Nuclear Magnetic Resonance in Nov. 2017 (DOI 10.1016/j.ssnmr.2017.10.001). In the paper we examine and summarize some of the exciting new insights into the molecular mechanisms behind protein misfolding and aggregation that have been enabled by a range of recent ssNMR studies.

This includes the various new amyloid structures deposited in the PDB, with links to these entries provided below:

• 5OQV
• 2M5N
• 2LNQ
• 2MVX
• 2MXU
• 5KK3
• 2NAO
• 2M4J
• 5W3N
• 2N1E
• 2N0A

Reference:
[1] Van der Wel, P.C.A. (2017) Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy. Solid State Nuclear Magnetic Resonance, 88: 1-14 (DOI 10.1016/j.ssnmr.2017.10.001)

Initially, free access to the full text can be obtained through this URL.

Congratulations to lab alum Dr. Hsiang-Kai Lin, graduate student Jennifer Boatz, and our collaborators locally and abroad! Our new publication describing the structure and properties of mutant huntingtin exon 1 fibrils has been published in the journal Nature Communications. The paper describes our ongoing studies of the mutant protein behind the devastating neurodegeneration in Huntington’s Disease. Biochemical and structural experiments show that mutant huntingtin exon 1 forms at least two types of neurotoxic aggregates with different internal structures.  Through the use of solid-state NMR spectroscopy and electron microscopy we look at the molecular details of these structural differences. Various other disease-related amyloid proteins have a similar tendency to form different types of aggregates (i.e. amyloid polymorphism), usually mediated by changes in the β-sheets of the amyloid assemblies they form. Surprisingly, in these huntingtin aggregates the polymorphism is due primarily to supramolecular change in the interactions among exposed and dynamic non-amyloid “flanking” domains. Importantly, it is these flanking domains that are targeted by protective chaperones, but they also mediate interactions with cellular membranes that may contribute to the toxic mechanism.

Publication info: Lin H-K, Boatz JC, Krabbendam IE, et al (2017) Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core. Nat Commun 8:15462.