Structures of PHR domains from Mus musculus Phr1 (Mycbp2) explain the loss-of-function mutation (Gly1092-->Glu) of the C. elegans ortholog RPM-1.
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 beta sandwich fold composed of 11 antiparallel beta-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.
Sampathkumar
Parthasarathy
P
Eli Lilly and Company, Lilly Biotechnology Center, 10300 Campus Point Drive, Suite 200, San Diego, CA 92121, USA. sampathkumarpa@lilly.com
Ozyurt
Sinem A
SA
Miller
Stacy A
SA
Bain
Kevin T
KT
Rutter
Marc E
ME
Gheyi
Tarun
T
Abrams
Benjamin
B
Wang
Yingchun
Y
Atwell
Shane
S
Luz
John G
JG
Thompson
Devon A
DA
Wasserman
Stephen R
SR
Emtage
J Spencer
JS
Park
Eun Chan
EC
Rongo
Christopher
C
Jin
Yishi
Y
Klemke
Richard L
RL
Sauder
J Michael
JM
Burley
Stephen K
SK
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D050505:Mutant Proteins; C409634:RPM-1 protein, C elegans; C532954:Mycbp2 protein, mouse; D044767:Ubiquitin-Protein Ligases