Cellular Localization and Characterization of Cytosolic Binding Partners for Gla Domain-containing Proteins PRRG4 and PRRG2

Yazicioglu, Mustafa N.; Monaldini, L.; Chu, Kirk; Khazi, Fayaz R.; Murphy, Samuel L.; Huang, Hsing Hua; Margaritis, Paris; High, Katherine A.

doi:10.1074/jbc.m113.484683

Cited by 14 publications

(19 citation statements)

References 23 publications

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“…Vitamin K acts as a cofactor to γ-glutamyl carboxylase (GGCX), an enzyme that catalyzes glutamic acid residues of specific proteins to γ-carboxyglutamic acid (Gla) to form Gla-containing proteins. These proteins, also called vitamin K-dependent proteins (VKDPs) [1][2][3][4][5][6][7][8][9][10][11], are listed in Table 1. When intake of vitamin K is insufficient, VKDPs are not fully activated and fail to execute their specific functions.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, vitamin K is expected to have various health benefits [13], preventing or alleviating cardiovascular disease, bone fracture, diabetes mellitus, cancer, liver disease, chronic kidney disease, immune disorder, neurological disease, and obesity. γ-carboxyglutamic acid-rich protein Inhibition of ectopic calcification, anti-inflammatory [5] Periostin Inhibition of ectopic calcification, tissue regeneration [6] Growth arrest-specific protein 6 Cell proliferation [7,8] Proline-rich γ-carboxy glutamyl proteins 1 and 2 Not well-known [9,10] γ-glutamyl carboxylase γ-glutamyl carboxylation of vitamin K-dependent proteins [11] Recently, vitamin K2 (MK-7) has been found to be highly effective in activating extrahepatic VKDPs at nutritional doses. In this study, we review the properties of MK-7.…”

Section: Introductionmentioning

confidence: 99%

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MK-7 and Its Effects on Bone Quality and Strength

Sato¹,

Inaba²,

Yamashita³

2020

Nutrients

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Vitamin K acts as a cofactor and is required for post-translational γ-carboxylation of vitamin K-dependent proteins (VKDP). The current recommended daily intake (RDI) of vitamin K in most countries has been established based on normal coagulation requirements. Vitamin K1 and menaquinone (MK)-4 has been shown to decrease osteocalcin (OC) γ-carboxylation at RDI levels. Among the several vitamin K homologs, only MK-7 (vitamin K2) can promote γ-carboxylation of extrahepatic VKDPs, OC, and the matrix Gla protein at a nutritional dose around RDI. MK-7 has higher efficacy due to its higher bioavailability and longer half-life than other vitamin K homologs. As vitamin K1, MK-4, and MK-7 have distinct bioactivities, their RDIs should be established based on their relative activities. MK-7 increases bone mineral density and promotes bone quality and strength. Collagen production, and thus, bone quality may be affected by MK-7 or MK-4 converted from MK-7. In this review, we comprehensively discuss the various properties of MK-7.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MK-7 and Its Effects on Bone Quality and Strength

Sato¹,

Inaba²,

Yamashita³

2020

Nutrients

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“…In addition to containing PDZ domains, the Magi family of scaffold proteins is unique among all other PDZ scaffolding proteins because it also contains WW domains (21). Sequence alignment demonstrated that Magi-1 WW domains are highly homologous to neural precursor cell expressed developmentally down-regulated protein 4-2 (Nedd4-2) WW domains (22), and the WW domains of Magi-1 have an absolute requirement for a PPXY motif for protein interaction compared with other WW domaincontaining proteins (23). Although there are many PDZ binding proteins known to associate with Magi-1, it remains unclear as to why Magi-1 contains WW domains.…”

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confidence: 99%

Magi‐1 scaffolds Na _v 1‐8 and Slack K _Na channels in dorsal root ganglion neurons regulating excitability and pain

et al. 2019

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Voltage‐dependent sodium (Nav) 1.8 channels regulate action potential generation in nociceptive neurons, identifying them as putative analgesic targets. Here, we show that Nav1.8 channel plasma membrane localization, retention, and stability occur through a direct interaction with the postsynaptic density‐95/discs large/zonula occludens‐l‐and WW domain‐containing scaffold protein called membrane‐associated guanylate kinase with inverted orientation (Magi)‐l. The neurophysiological roles of Magi‐1 are largely unknown, but we found that dorsal root ganglion (DRG)‐specific knockdown of Magi‐1 attenuated thermal nociception and acute inflammatory pain and produced deficits in Nav1.8 protein expression. A competing cell‐penetrating peptide mimetic derived from the Nav1.8 WW binding motif decreased sodium currents, reduced Nav1.8 protein expression, and produced hypoexcitability. Remarkably, a phosphorylated variant of the very same peptide caused an opposing increase in Nav1.8 surface expression and repetitive firing. Likewise, in vivo, the peptides produced diverging effects on nocifensive behavior. Additionally, we found that Magi‐1 bound to sequence like a calcium‐activated potassium channel sodium‐activated (Slack) potassium channels, demonstrating macrocomplexing with Nav1.8 channels. Taken together, these findings emphasize Magi‐1 as an essential scaffold for ion transport in DRG neurons and a central player in pain.—Pryce, K. D., Powell, R., Agwa, D., Evely, K. M., Sheehan, G. D., Nip, A., Tomasello, D. L., Gururaj, S., Bhattacharjee, A. Magi‐1 scaffolds Nav1.8 and Slack KNa channels in dorsal root ganglion neurons regulating excitability and pain. FASEB J. 33, 7315–7330 (2019). http://www.fasebj.org

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“…The vertebrate proline rich and Gla domain genes PRRG1-4, also known as PRGP1, PRGP2, TMG3 and TMG4 respectively [ 16 , 17 ], encode short transmembrane proteins. PRRG4 protein has been found in the Golgi apparatus and at the cell surface [ 18 – 20 ]. All PRRG proteins contain a Gla domain in which glutamic acid (Glu) residues are γ-carboxylated in the endoplasmic reticulum by γ-glutamyl carboxylase (GGCX) [ 21 , 22 ] to form γ-carboxyglutamate (Gla) residues.…”

Section: Introductionmentioning

confidence: 99%

“…The PY motifs of Comm1 interact with the WW domain of the Nedd4 E3 ubiquitin-protein ligase [ 9 ]. The PY motifs of the human PRRG4 protein also interact with the WW domain of Nedd4 [ 18 ]. The interaction with Nedd4 is only implicated in endocytosis of Robo from the cell surface and not in regulation of Robo exocytosis [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene

2017

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WAGR syndrome is characterized by Wilm’s tumor, aniridia, genitourinary abnormalities and intellectual disabilities. WAGR is caused by a chromosomal deletion that includes the PAX6, WT1 and PRRG4 genes. PRRG4 is proposed to contribute to the autistic symptoms of WAGR syndrome, but the molecular function of PRRG4 genes remains unknown. The Drosophila commissureless (comm) gene encodes a short transmembrane protein characterized by PY motifs, features that are shared by the PRRG4 protein. Comm intercepts the Robo axon guidance receptor in the ER/Golgi and targets Robo for degradation, allowing commissural axons to cross the CNS midline. Expression of human Robo1 in the fly CNS increases midline crossing and this was enhanced by co-expression of PRRG4, but not CYYR, Shisa or the yeast Rcr genes. In cell culture experiments, PRRG4 could re-localize hRobo1 from the cell surface, suggesting that PRRG4 is a functional homologue of Comm. Comm is required for axon guidance and synapse formation in the fly, so PRRG4 could contribute to the autistic symptoms of WAGR by disturbing either of these processes in the developing human brain.

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Cellular Localization and Characterization of Cytosolic Binding Partners for Gla Domain-containing Proteins PRRG4 and PRRG2

Cited by 14 publications

References 23 publications

MK-7 and Its Effects on Bone Quality and Strength

MK-7 and Its Effects on Bone Quality and Strength

Magi‐1 scaffolds Na _v 1‐8 and Slack K _Na channels in dorsal root ganglion neurons regulating excitability and pain

The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene

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Cellular Localization and Characterization of Cytosolic Binding Partners for Gla Domain-containing Proteins PRRG4 and PRRG2

Cited by 14 publications

References 23 publications

MK-7 and Its Effects on Bone Quality and Strength

MK-7 and Its Effects on Bone Quality and Strength

Magi‐1 scaffolds Na v 1‐8 and Slack K Na channels in dorsal root ganglion neurons regulating excitability and pain

The WAGR syndrome gene PRRG4 is a functional homologue of the commissureless axon guidance gene

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Magi‐1 scaffolds Na _v 1‐8 and Slack K _Na channels in dorsal root ganglion neurons regulating excitability and pain