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

doi:10.1016/j.jmb.2010.02.017

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 journal › Article › peer-review

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 language	English (US)
Pages (from-to)	883-892
Number of pages	10
Journal	Journal of Molecular Biology
Volume	397
Issue number	4
DOIs	https://doi.org/10.1016/j.jmb.2010.02.017
State	Published - Apr 2010
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Biophysics
Structural Biology
Molecular Biology

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10.1016/j.jmb.2010.02.017

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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

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

@article{9e9d62a247e241108e7223515e9e183f,

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

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.",

keywords = "Mycbp2, PHR domain, Phr1, RPM-1, Synaptic development and axon guidance",

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

note = "Funding Information: This work was carried out at SGX Pharmaceuticals, Inc., and Eli Lilly and Company. Funding for this work was provided by National Institutes of Health Grants U54 GM074945 (PI: S.K.B.) and NS035546 (PI: Y.J.). Use of the Advanced Photon Source (APS) was supported by the U.S. Department of Energy, Office of Basic Energy Sciences. Use of the LRL-CAT beamline facilities at Sector 31 of the APS was provided by Eli Lilly and Company, which operates the facility. Authors declare no financial interest related to the work described in this communication. ",

year = "2010",

month = apr,

doi = "10.1016/j.jmb.2010.02.017",

language = "English (US)",

volume = "397",

pages = "883--892",

journal = "Journal of Molecular Biology",

issn = "0022-2836",

publisher = "Academic Press Inc.",

number = "4",

}

TY - JOUR

T1 - Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092→Glu) of the C. elegans ortholog RPM-1

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.

N1 - Funding Information: This work was carried out at SGX Pharmaceuticals, Inc., and Eli Lilly and Company. Funding for this work was provided by National Institutes of Health Grants U54 GM074945 (PI: S.K.B.) and NS035546 (PI: Y.J.). Use of the Advanced Photon Source (APS) was supported by the U.S. Department of Energy, Office of Basic Energy Sciences. Use of the LRL-CAT beamline facilities at Sector 31 of the APS was provided by Eli Lilly and Company, which operates the facility. Authors declare no financial interest related to the work described in this communication.

PY - 2010/4

Y1 - 2010/4

N2 - 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.

AB - 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.

KW - Mycbp2

KW - PHR domain

KW - Phr1

KW - RPM-1

KW - Synaptic development and axon guidance

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

Abstract

Keywords

ASJC Scopus subject areas

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