Van der Wel lab at the Biophysical Society Meeting in San Francisco!

This coming week the Van der Wel lab will be represented at the annual meeting of the Biophysical Society, taking place in San Francisco. As summarized below, a recurring theme in the presented work will be the impact of oxidative damage in health and disease.

BPS2018 Logo
Dr. Mingyue Li will present her studies of mitochondrial protein-lipid interactions during her platform session talk on Monday Feb. 19 (1130AM; 999-PLAT). She will talk about the structure and dynamics of the cardiolipin-cytochrome c complex that is implicated in the early stages of mitochondrial apoptosis. This protein/lipid complex features a peripherally bound protein that facilitates the oxidation of poly-unsaturated cardiolipin lipids.

Jennifer Boatz will present a poster on Feb 21st (2815-Pos; B23) on her use of magic-angle-spinning NMR and electron microscopy to probe the aggregated state of apolipoprotein A1, in presence and absence of methionine oxidation. Aggregated ApoA1 is a prominent component of deposits formed during atherosclerosis. For more information see Jennifer’s poster and our in-press collaborative publication in the FASEB Journal.

Publication: Amyloid seeding by oxidized apolipoprotein A-I

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.

Publication: Molecular underpinnings of amyloid fibril twisting.

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

Publication: Review on structural and mechanistic aspects of protein aggregation.

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:

[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.

Publication: Structure and polymorphism of toxic huntingtin exon1 fibrils (Nature Comm.)

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.


Postdoctoral positions available

Postdoctoral positions are available in our lab or the lab of our  collaborator Rajesh Ramachandran at Case Western Reserve University in nearby Cleveland. Potential projects focus on polyglutamine-related protein aggregation or mitochondrial protein-lipid interactions involved in either mitochondrial apoptosis or mitochondrial fission.

More information about the collaborative position can be found here. Otherwise, please contact Patrick van der Wel via email with your CV and a description of your research background and interests. A background in NMR is strongly preferred.


Publication: Amorphous protein aggregates related to cataracts.

Congratulations to Jennifer Boatz, Dr. Mingyue Li and our collaborators in the Gronenborn lab for the publication of our new paper on cataract-related protein aggregation. Our newly published report in Nature Communications looks at the structure of a mutant protein (P23T γD crystallin) associated with inherited cataract disease, when it is aggregated. Interestingly, the same protein forms very different kinds of deposits depending on the conditions under which it aggregates: a common type of aggregate “polymorphism”. In many studies of protein aggregation, the protein of interest is made to form aggregates by exposure to acidic conditions. This cataract protein also aggregates well under such conditions, which cause it to form worm-like amyloid fibrils. However, Jennifer also looked at the protein aggregation that happens at neutral pH, such as is present in the eye. Interestingly, this results in amorphous-looking deposits that are dramatically different from canonical amyloid. Despite looking amorphous, the aggregates give beautiful solid-state NMR spectra that reveal their internal structure to be well ordered and seemingly very similar to the native state of the protein. (Which is not the case in amyloids that form due to extensive misfolding of other proteins) The paper also talks about the potential implications for our thinking about how the cataract-related aggregation process may take place, and how such information may be useful for optimal anti-cataract drug design and screening efforts.

The full reference for the paper: Boatz, J.C., Whitley, M.J., Li, M., Gronenborn, A.M., & Van der Wel, P.C.A. (2017) Cataract-associated P23T γD-crystallin retains a native-like fold in amorphous-looking aggregates formed at physiological pH. Nat. Commun. 8:15137.

PS. Jennifer will at the upcoming FASEB SRC meeting on Protein Aggregation in Health and Disease to present this exciting work in person. We hope to see you there!

New Protein Misfolding Disease center featured in Pitt Chronicle.

The forthcoming official opening of the new Center for Protein Conformational Diseases was featured in the Pitt Chronicle in an article entitled “New Pitt Center Will Study Diseases Linked to Misshapen Proteins“. The Center’s website is already online, here, with listings of the faculty members and an overview of an impressive list of existing collaborative publications. This exciting new initiative further strengthens existing programs such the Pittsburgh Institute for Neurodegenerative Diseases (PIND) and the Brain Institute.


Publication: Ultracentrifugal packing of biological MAS NMR samples.

Congratulations to Abhishek and Jennifer on having our new paper accepted for publication in the Journal of Biomolecular NMR. In it Abhishek describes the use of custom-built ultracentrifuge sample packing devices for the preparation of solid-state NMR samples.

Publication info:

On the use of ultracentrifugal devices for routine sample preparation in biomolecular magic-angle-spinning NMR. Mandal, A., Boatz, J.C., Wheeler, T., and Van der Wel, P.C.A. (2017) J. Biomol. NMR in press. DOI

Access it via this sharing link:


Publication: Backbone engineering within a latent β-hairpin structure to design inhibitors of polyglutamine amyloid formation. (J. Mol. Biol.)


Our new publication together with our collaborators in the Wetzel and Horne groups is now available online at the Journal of Molecular Biology:

  • Backbone engineering within a latent β-hairpin structure to design inhibitors of polyglutamine amyloid formation. Kar, K., Baker, M.A., Lengyel, G.A., Hoop, C.L., Kodali, R., Byeon, I-J., Horne, W.S., Van der Wel, P.C.A., and Wetzel, R., (2016) J. Mol. Biol. in press (DOI)

In this work, Karunakar Kar and co-workers (including Cody Hoop from our lab) combined various techniques to design and test designer-inhibitors against polyQ aggregation. The work highlights the value of structural and mechanistic understanding of the polyglutamine misfolding and aggregation process in such endeavors. (Some of these structural insights were derived from current and prior solid-state NMR studies.)