In humans this phosphorylated trisaccharide is attached to an L-threonine residue of alpha-dystroglycan, an extracellular peripheral glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains, and is important for its activity.
In humans this phosphorylated trisaccharide is attached to an L-threonine residue of alpha-dystroglycan, an extracellular peripheral glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains, and is important for its activity.
enzyme POMK can efficiently phosphorylate the GalNAc-beta3-GlcNAc-beta4-Man trisaccharide. GalNAc-beta3-GlcNAc-beta4-Man is recognized by a surface groove, and the GalNAc-beta3-GlcNAc moiety mediates the majority of interactions with POMK. POMK specifically recognizes GalNAc-beta3-GlcNAc-beta4-mannose
enzyme POMK can efficiently phosphorylate the GalNAc-beta3-GlcNAc-beta4-Man trisaccharide. GalNAc-beta3-GlcNAc-beta4-Man is recognized by a surface groove, and the GalNAc-beta3-GlcNAc moiety mediates the majority of interactions with POMK. POMK specifically recognizes GalNAc-beta3-GlcNAc-beta4-mannose
enzyme POMK can efficiently phosphorylate the GalNAc-beta3-GlcNAc-b4-Man trisaccharide. GalNAc-beta3-GlcNAc-beta4-Man is recognized by a surface groove, and the GalNAc-beta3-GlcNAc moiety mediates the majority of interactions with POMK
enzyme POMK can efficiently phosphorylate the GalNAc-beta3-GlcNAc-b4-Man trisaccharide. GalNAc-beta3-GlcNAc-beta4-Man is recognized by a surface groove, and the GalNAc-beta3-GlcNAc moiety mediates the majority of interactions with POMK
bi-allelic pathogenic variants in POMK are the cause of a broad spectrum of alpha-dystroglycanopathies. Walker-Warburg syndrome (WWS) is a rare form of alpha-dystroglycanopathy characterized by muscular dystrophy and severe malformations of the CNS and eyes. Twins that both harbor a homozygous nonsense mutation c.640C>T, p.214* in gene POMK show a phenotype with severe CNS malformations (hydrocephalus, cortical malformation, hypoplastic cerebellum, and most prominently occipital meningocele), eye malformations and highly elevated creatine kinase, indicating the clinical diagnosis of a congenital muscular dystrophy (alpha-dystroglycanopathy). Important role for POMK in the pathogenesis of meningoencephalocele. Important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families. Only five show the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. The phenotypic and mutational spectrum of POMK-associated WWS analysis provides evidence of the broad phenotypic variability of POMK-associated disease. Clinical phenotype, overview
POMK mutations cause a spectrum of congenital and limb-girdle muscular dystrophies, including the most severe presentation known as the Walker-Warburg syndrome, which is associated with brain and eye abnormalities and death in early childhood. Disease-causing mutations, overview
several missense mutations of the POMK catalytic domain are known to cause a severe congenital muscular dystrophy, Walker-Warburg syndrome. Aberrant O-mannosylation of alpha-DG leads to severe congenital muscular dystrophies due to detachment of ECM proteins from the basal membrane. Disease mutation mapping onto POMK structure
enzyme POMK plays a critical role for the biosynthesis of functional alpha-dystroglycan (alph-DG), alpha-DG is a subunit of the dystroglycan complex, and binds to basement membrane molecules such as laminin to connect the extracellular matrix with the actin cytoskeleton. alpha-DG is also a receptor for human pathogens
enzyme POMK plays a critical role for the biosynthesis of functional alpha-dystroglycan (alph-DG), alpha-DG is a subunit of the dystroglycan complex, and binds to basement membrane molecules such as laminin to connect the extracellular matrix with the actin cytoskeleton. alpha-DG is also a receptor for human pathogens
orchestration of the multiple enzymes engaged in O-mannose glycan synthesis provides a matriglycan on alpha-dystroglycan (alpha-DG) which attracts extracellular matrix (ECM) proteins such as laminin. phosphorylation at C6-position of O-mannose catalyzed by protein O-mannosyl kinase (POMK) is a crucial step in the biosynthetic pathway of O-mannose glycan
phosphorylation at C6-position of O-mannose catalyzed by protein O-mannosyl kinase (POMK) is a crucial step in the biosynthetic pathway of O-mannose glycan
POMK encodes protein-O-mannose kinase, which is required for proper glycosylation and function of the dystroglycan complex and is crucial for extracellular matrix composition
SGK196 is a protein O-mannose kinase involved in an indispensable phosphorylation step during laminin-binding glycan synthesis on alpha-dystroglycan (alpha-DG). SGK196 functions as a glycosylationspecific kinase. SGK196 is involved in the phosphorylation of M3 glycan mannose on the C-6 position within the M3 O-glycan of alpha-dystroglycan (alpha-DG). alpha-DG is a peripheral membrane protein, serving as a receptor for various extracellular matrix components, such as laminin, agrin, perlecan. Extensive glycosylation of alpha-DG is essential for its binding to extracellular matrix ligands. N-glycosylated SGK196 suppresses cell migration, invasion, and metastasis in breast cancer cells, particularly in the basal-like breast cancer (BLBC) type. In addition, enzyme SGK196 N-glycosylation performs the regulatory function through the PI3K/AKT/GSK3beta signaling pathway. N-glycosylated SGK196 plays suppression roles in BLBC metastases, SGK196 N-glycosylation is required for repression of metastasis
the 'pseudokinase' SgK196 is a protein O-mannose kinase (POMK) that catalyzes an essential phosphorylation step during biosynthesis of the laminin-binding glycan on alpha-dystroglycan
the 'pseudokinase' SgK196 is a protein O-mannose kinase (POMK) that catalyzes an essential phosphorylation step during biosynthesis of the laminin-binding glycan on alpha-dystroglycan
the POMK catalytic domain shows a typical protein kinase fold consisting of N- and C-lobes. Mannose residue binds to POMK mainly via the hydroxyl group at C2-position, differentiating from other monosaccharide residues. Intriguingly, the two amino acid residues K92 and D228, interacting with the triphosphate group of ATP, are donated from atypical positions in the primary structure. Protein O-mannosyl kinase (POMK) catalytic domain shows a typical kinase fold, recombinant murne POMK catalytic domain structure, overview. Docking model of POMK in complex with AMP-PNP and the trisaccharide unit (GalNAcbeta1-3GlcNAcbeta1-4Man) and molecular dynamics simulations
the structure of protein O-mannose kinase reveals a unique active site architecture. The active site of POMK is established by residues located in non-canonical positions and is stabilized by a disulfide bridge. Seven conserved Cys are present in POMK homologues, and six of them are involved in forming three pairs of disulfide bridges in DrPOMK. Cys53-Cys66 is located in a long loop in the backside of the N-lobe. Cys72-Cys139 connects helix alphaB and strand beta4. Cys201-Cys241 links the catalytic loop with the activation segment. Cys310 alone exists as a free cysteine and is buried in the C-lobe, not exposed to the solvent. DrPOMK kinase has a bilobal architecture. In POMK, a Ser (Ser106DrPOMK) occupies the position of the critical Lys72PKA in strand beta3. The critical role of this Lys in DrPOMK is instead served by Lys91_DrPOMK located at the beginning of strand beta2 that reaches into the active site and interacts with the phosphate groups of ADP. Another important Lys involved in nucleotide-binding is Lys208_DrPOMK located in helix alphaCL, it interacts with the AlF3 group that mimics the transition state gamma-phosphate of ATP
the structure of protein O-mannose kinase reveals a unique active site architecture. The active site of POMK is established by residues located in non-canonical positions and is stabilized by a disulfide bridge. Seven conserved Cys are present in POMK homologues, and six of them are involved in forming three pairs of disulfide bridges in DrPOMK. Cys53-Cys66 is located in a long loop in the backside of the N-lobe. Cys72-Cys139 connects helix alphaB and strand beta4. Cys201-Cys241 links the catalytic loop with the activation segment. Cys310 alone exists as a free cysteine and is buried in the C-lobe, not exposed to the solvent. DrPOMK kinase has a bilobal architecture. In POMK, a Ser (Ser106DrPOMK) occupies the position of the critical Lys72PKA in strand beta3. The critical role of this Lys in DrPOMK is instead served by Lys91_DrPOMK located at the beginning of strand beta2 that reaches into the active site and interacts with the phosphate groups of ADP. Another important Lys involved in nucleotide-binding is Lys208_DrPOMK located in helix alphaCL, it interacts with the AlF3 group that mimics the transition state gamma-phosphate of ATP
as a type II transmembrane protein, SGK196 consists of a cytoplasmic tail, one transmembrane helix, and a luminal domain. Lack of functional motifs of protein kinases including Asp-Phe-Gly (DFG), His-Arg-Asp (HRD) and conserved Lys residues in the primary structure of SGK196
the POMK catalytic domain takes a typical protein kinase fold consisting of N- and C-lobes. The N-lobe goes from C54 to P152 and comprises five beta-strands arranged in an antiparallel beta-sheet with two alpha-helices (alpha1-2), whereas C-lobe is from L153 to L337 and is composed of nine alpha-helices (alpha3-11) with a beta-hairpin (beta6-7)
SGK196 is primarily modified by N-glycosylation in breast cancer cells. N-glycosylation of SGK196 leads to suppression of cell migration, invasion, and metastasis in breast cancer cells, particularly in the basal-like breast cancer (BLBC) type. In addition, enzyme SGK196 N-glycosylation performs the regulatory function through the PI3K/AKT/GSK3beta signaling pathway. N-glycosylated SGK196 plays suppression roles in BLBC metastases. The phosphorylation of the enzyme can be abolished by RPN1 knockout
murine POMK catalytic domain (residue 45-349) possesses three potential N-glycosylation sites, N66, N164 and N219, which are not conserved among species
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified enzyme POMK in complex with Mg2+ ions, ADP, aluminum fluoride, and the GalNAc-beta3-GlcNAc-beta4-Man trisaccharide substrate, X-ray diffraction structure determination and analysis at 2.0 A resolution
site-directed mutagenesis, the catalytic activity is restored in the double mutant, which reinstalls the Lys in strand beta3. In fact, this mutant, having both the Gly-rich loop and the beta3 Lys restored, has enhanced kinase activity in vitro compared to the wild-type enzyme
site-directed mutagenesis, N66Q is located in the N-terminal loop region and close to a symmetry-related molecule, while N164Q is located at the alpha2-alpha3 loop
generation of the SGK196-4NQ mutant with several N to Q amino acid exchanges. The PNGase F or Endo H treatment assay also indicates that SGK196-4NQ mutant is totally deglycosylated. The NQ mutations do not affect the stability or the subcellular localization of SGK196 protein in both MDA-MB-231 and BT-549 cells. SGK196 depletion in both MDA-MB-231 and BT-549 cells significantly increases cell migration and invasion. Re-supply of wild-type SGK196 in MDA-MB-231shSGK196 cell line significantly decreases the number of lung metastasis nodules, when compared with the empty vector, by inhibiting the PI3K/AKT/GSK3beta signaling pathway
important role for POMK in the pathogenesis of meningoencephalocele. Only eight different pathogenic POMK variants have been published so far, detected in eight families. Only five show the severe WWS phenotype, suggesting that POMK-associated WWS is an extremely rare disease. The phenotypic and mutational spectrum of POMK-associated WWS analysis provides evidence of the broad phenotypic variability of POMK-associated disease
gene pomk, recombinant expression of th POMK catalytic domain in HEK-293 cells as a homogeneous glycoprotein with Man5GlcNAc2 structure, the deconvoluted ESI-MS spectrum showed three peaks, which correspond to singly N-glycosylated, doubly N-glycosylated and triply N-glycosylated proteins: N66 and N164 are partially glycosylated, whereas N219 is fully glycosylated