All Publications


  • Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling. Molecular cell Wigington, C. P., Roy, J. n., Damle, N. P., Yadav, V. K., Blikstad, C. n., Resch, E. n., Wong, C. J., Mackay, D. R., Wang, J. T., Krystkowiak, I. n., Bradburn, D. A., Tsekitsidou, E. n., Hong, S. H., Kaderali, M. A., Xu, S. L., Stearns, T. n., Gingras, A. C., Ullman, K. S., Ivarsson, Y. n., Davey, N. E., Cyert, M. S. 2020

    Abstract

    Short linear motifs (SLiMs) drive dynamic protein-protein interactions essential for signaling, but sequence degeneracy and low binding affinities make them difficult to identify. We harnessed unbiased systematic approaches for SLiM discovery to elucidate the regulatory network of calcineurin (CN)/PP2B, the Ca2+-activated phosphatase that recognizes LxVP and PxIxIT motifs. In vitro proteome-wide detection of CN-binding peptides, in vivo SLiM-dependent proximity labeling, and in silico modeling of motif determinants uncovered unanticipated CN interactors, including NOTCH1, which we establish as a CN substrate. Unexpectedly, CN shows SLiM-dependent proximity to centrosomal and nuclear pore complex (NPC) proteins-structures where Ca2+ signaling is largely uncharacterized. CN dephosphorylates human and yeast NPC proteins and promotes accumulation of a nuclear transport reporter, suggesting conserved NPC regulation by CN. The CN network assembled here provides a resource to investigate Ca2+ and CN signaling and demonstrates synergy between experimental and computational methods, establishing a blueprint for examining SLiM-based networks.

    View details for DOI 10.1016/j.molcel.2020.06.029

    View details for PubMedID 32645368

  • A novel quantitative real-time PCR diagnostic assay for seal heartworm (Acanthocheilonema spirocauda) provides evidence for possible infection in the grey seal (Halichoerus grypus) INTERNATIONAL JOURNAL FOR PARASITOLOGY-PARASITES AND WILDLIFE Keroack, C. D., Williams, K. M., Fessler, M. K., DeAngelis, K. E., Tsekitsidou, E., Tozloski, J. M., Williams, S. A. 2018; 7 (2): 147–54

    Abstract

    The distinct evolutionary pressures faced by Pinnipeds have likely resulted in strong coevolutionary ties to their parasites (Leidenberger et al., 2007). This study focuses on the phocid seal filarial heartworm species Acanthocheilonema spirocauda. A. spirocauda is known to infect a variety of phocid seals, but does not appear to be restricted to a single host species (Measures et al., 1997; Leidenberger et al., 2007; Lehnert et al., 2015). However, to date, seal heartworm has never been reported in grey seals (Halichoerus grypus) (Measures et al., 1997; Leidenberger et al., 2007; Lehnert et al., 2015). The proposed vector for seal heartworm is Echinophthirius horridus, the seal louse. Seal lice are known to parasitize a wide array of phocid seal species, including the grey seal. With the advent of climate change, disease burden is expected to increase across terrestrial and marine mammals (Harvell et al., 2002). Accordingly, increased prevalence of seal heartworm has recently been reported in harbor seals (Phoca vitulina) (Lehnert et al., 2015). Thus, the need for improved, rapid, and cost-effective diagnostics is urgent. Here we present the first A. spirocauda-specific rapid diagnostic test (a quantitative real-time PCR assay), based on a highly repetitive genomic DNA repeat identified using whole genome sequencing and subsequent bioinformatic analysis. The presence of an insect vector provides the opportunity to develop a multifunctional diagnostic tool that can be used not only to detect the parasite directly from blood or tissue specimens, but also as a molecular xenomonitoring (XM) tool that can be used to assess the epidemiological profile of the parasite by screening the arthropod vector. Using this assay, we provide evidence for the first reported case of seal heartworm in a grey seal.

    View details for DOI 10.1016/j.ijppaw.2018.04.001

    View details for Web of Science ID 000438781400005

    View details for PubMedID 29988808

    View details for PubMedCentralID PMC6031957