Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092→Glu) of the C. elegans ortholog RPM-1

Parthasarathy Sampathkumar, Sinem A. Ozyurt, Stacy A. Miller, Kevin T. Bain, Marc E. Rutter, Tarun Gheyi, Benjamin Abrams, Yingchun Wang, Shane Atwell, John G. Luz, Devon A. Thompson, Stephen R. Wasserman, J. Spencer Emtage, Eun Chan Park, Christopher Rongo, Yishi Jin, Richard L. Klemke, J. Michael Sauder, Stephen K. Burley

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

PHR [PAM (protein associated with Myc)-HIW (Highwire)-RPM-1 (regulator of presynaptic morphology 1)] proteins are conserved, large multi-domain E3 ubiquitin ligases with modular architecture. PHR proteins presynaptically control synaptic growth and axon guidance and postsynaptically regulate endocytosis of glutamate receptors. Dysfunction of neuronal ubiquitin-mediated proteasomal degradation is implicated in various neurodegenerative diseases. PHR proteins are characterized by the presence of two PHR domains near the N-terminus, which are essential for proper localization and function. Structures of both the first and second PHR domains of Mus musculus (mouse) Phr1 (MYC binding protein 2, Mycbp2) have been determined, revealing a novel β sandwich fold composed of 11 antiparallel β-strands. Conserved loops decorate the apical side of the first PHR domain (MmPHR1), yielding a distinct conserved surface feature. The surface of the second PHR domain (MmPHR2), in contrast, lacks significant conservation. Importantly, the structure of MmPHR1 provides insights into a loss-of-function mutation, Gly1092 → Glu, observed in the Caenorhabditis elegans ortholog RPM-1.

Original languageEnglish (US)
Pages (from-to)883-892
Number of pages10
JournalJournal of Molecular Biology
Volume397
Issue number4
DOIs
StatePublished - Apr 2010

Keywords

  • Mycbp2
  • PHR domain
  • Phr1
  • RPM-1
  • Synaptic development and axon guidance

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Sampathkumar, P., Ozyurt, S. A., Miller, S. A., Bain, K. T., Rutter, M. E., Gheyi, T., Abrams, B., Wang, Y., Atwell, S., Luz, J. G., Thompson, D. A., Wasserman, S. R., Emtage, J. S., Park, E. C., Rongo, C., Jin, Y., Klemke, R. L., Sauder, J. M., & Burley, S. K. (2010). Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092→Glu) of the C. elegans ortholog RPM-1. Journal of Molecular Biology, 397(4), 883-892. https://doi.org/10.1016/j.jmb.2010.02.017