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 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Carrier Proteins
Mutation
Proteins
Ubiquitin-Protein Ligases
Caenorhabditis elegans
Glutamate Receptors
Ubiquitin
Endocytosis
Neurodegenerative Diseases
Growth

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092→Glu) of the C. elegans ortholog RPM-1. / Sampathkumar, Parthasarathy; Ozyurt, Sinem A.; Miller, Stacy A.; Bain, Kevin T.; Rutter, Marc E.; Gheyi, Tarun; Abrams, Benjamin; Wang, Yingchun; Atwell, Shane; Luz, John G.; Thompson, Devon A.; Wasserman, Stephen R.; Emtage, J. Spencer; Park, Eun Chan; Rongo, Christopher; Jin, Yishi; Klemke, Richard L.; Sauder, J. Michael; Burley, Stephen K.

In: Journal of Molecular Biology, Vol. 397, No. 4, 04.2010, p. 883-892.

Research output: Contribution to journalArticle

Sampathkumar, P, Ozyurt, SA, Miller, SA, Bain, KT, Rutter, ME, Gheyi, T, Abrams, B, Wang, Y, Atwell, S, Luz, JG, Thompson, DA, Wasserman, SR, Emtage, JS, Park, EC, Rongo, C, Jin, Y, Klemke, RL, Sauder, JM & Burley, SK 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, vol. 397, no. 4, pp. 883-892. https://doi.org/10.1016/j.jmb.2010.02.017
Sampathkumar, Parthasarathy ; Ozyurt, Sinem A. ; Miller, Stacy A. ; Bain, Kevin T. ; Rutter, Marc E. ; Gheyi, Tarun ; Abrams, Benjamin ; Wang, Yingchun ; Atwell, Shane ; Luz, John G. ; Thompson, Devon A. ; Wasserman, Stephen R. ; Emtage, J. Spencer ; Park, Eun Chan ; Rongo, Christopher ; Jin, Yishi ; Klemke, Richard L. ; Sauder, J. Michael ; Burley, Stephen K. / Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092→Glu) of the C. elegans ortholog RPM-1. In: Journal of Molecular Biology. 2010 ; Vol. 397, No. 4. pp. 883-892.
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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.",
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AU - Sampathkumar, Parthasarathy

AU - Ozyurt, Sinem A.

AU - Miller, Stacy A.

AU - Bain, Kevin T.

AU - Rutter, Marc E.

AU - Gheyi, Tarun

AU - Abrams, Benjamin

AU - Wang, Yingchun

AU - Atwell, Shane

AU - Luz, John G.

AU - Thompson, Devon A.

AU - Wasserman, Stephen R.

AU - Emtage, J. Spencer

AU - Park, Eun Chan

AU - Rongo, Christopher

AU - Jin, Yishi

AU - Klemke, Richard L.

AU - Sauder, J. Michael

AU - Burley, Stephen K.

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