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FLASH GENE
Symbol ASPH contributors: mct/npt/pgu - updated : 09-05-2016
HGNC name aspartate beta-hydroxylase
HGNC id 757
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • extended N-terminus with potential transmembrane (TM ) type II signal anchor domain directing the catalytic domain into the endoplasmic reticulum, N terminus comprising &
    • 8764;26 amino acids (a truncation of these AAs prevents junctional accumulation of ASPH)
  • a Ca(2+)-binding EF-hand motif
  • a compact C terminus catalytic domain, and Ca2+-sensing role of junctate was demonstrated after uncovering an EF-hand domain in the ER-luminal region, in its C terminus
    • mono polymer monomer
    HOMOLOGY
    interspecies homolog to murine Asph
    intraspecies homolog to TRDN
    Homologene
    FAMILY
  • aspartyl/asparaginyl beta-hydroxylase family
    • CATEGORY enzyme , structural protein , transport carrier
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,lumen
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    text
  • potentially cleaved into a 56kDa protein in the lumen of ER
  • with SERCA2 co-localized in the sarcoplasmic reticulum of cardiomyocytes
  • intra-sarcoplasmic reticulum (SR) protein
  • inserted into the membrane of the sarcoplasmic reticulum (SR) Ca(2+) store where it modifies Ca(2+) signalling in the heart and skeletal muscle
    • basic FUNCTION
  • potentially involved in divalent cation binding and protein-protein interaction for a number of vitamin K dependent proteins, like proC, F7, F9, F10, complement factors C1R, C1S
  • may play an important role in the regulation of SR Ca(2+) cycling through the interaction with ATP2A2 in the murine heart
  • SR membrane protein, which is part of the SR Ca(2+) release quaternary structure that also includes the ryanodine receptor, triadin and calsequestrin
  • serves as a bridge between calsequestrin and the Ca(2+) release channel, ryanodine receptor
  • involved in calcium homeostasis with calsquestrin, triadin, ryanodine receptor
  • involved in calcium homeostasis in eukaryotic cells
  • essential factor in maintaining normal cardiac Ca handling and cardiac function
  • triadin and junctin are integral sarcoplasmic reticulum membrane proteins that form a macromolecular complex with the skeletal muscle ryanodine receptor (RYR1)
  • has a role in maintaining sarcoplasmic reticulum Ca2+ store size in myotubes
  • ASPH and TRDN each activate skeletal ryanodine receptors but ASPH alone mediates functional interactions with CASQ1
  • normally acts as an activator of RYR channels at low luminal [Ca(2+)], and as an inhibitor at high luminal [Ca(2+)]
  • Ca2+-sensing ER protein, and structural component of the ER-PM junctions where ORAI1 and STIM1 cluster and interact in T cells
  • cell surface protein that catalyzes the hydroxylation of epidermal growth factor (EGF)-like repeats in Notch receptors and ligands
  • mediates an alternative mechanism for generating localized Ca(2+) elevations within cells, promoting Ca(2+) release from internal stores recruited to phagosomes, thereby boosting phagocytosis
    • CELLULAR PROCESS protein, post translation
    PHYSIOLOGICAL PROCESS
    text hydroxylation of ASP or ASN in EGF-like domains of several proteins
    PATHWAY
    metabolism aminoacid
    signaling
    a component
  • CASQ2, TRDN and ASPH form a protein complex that is associated with cardiac ryanodine receptor 2 (RYR2) SR Ca(2+) release channels
  • forms a quaternary protein complex with the ryanodine receptor, calsequestrin, and triadin in the SR lumen of cardiac muscle
  • indirect role for triadin in regulating myoplasmic Ca(2+) homeostasis and organizing the molecular complex of the triad but not in regulating skeletal-type excitation-contraction coupling
  • Ca(2+)-sensing ER protein, and is a structural component of the ER-plasma membrane junctions where ORAI1 and STIM1 cluster and interact in T cells
  • plays an additional role in STIM1 recruitment by defining the ER-PM junctions for clustering of ORAI1 and STIM1 in a Ca2+-dependent manner
  • mediates an alternative mechanism for generating localized Ca(2+) elevations within cells, promoting Ca(2+) release from internal stores recruited to phagosomes, thereby boosting phagocytosis
    • INTERACTION
    DNA
    RNA
    small molecule metal binding,
  • iron Fe2+
    • protein
  • interacting with ATP2A2 (binding of the C-terminal region of junctate (AAs 79-270) and luminal domain of ATP2A2 (AAs 70-89)
  • constant interactions between CASQ2 and ASPH, regardless of the SR Ca(2+) concentration, implying that ASPH is an essential component of the CASQ2 scaffold
  • ASPH is an interacting partner of ORAI1-STIM1 complex
  • TRDN and ASPH are structurally related transmembrane proteins thought to be key mediators of structural and functional interactions between calsequestrin (CASQ1) and ryanodine receptor (RyRs) at the junctional sarcoplasmic reticulum
  • C-terminal domain of ASPH binds to residues including the S1-S2 linker of RYR1 and N-terminal domain of ASPH binds between RYR1 residues 1078 and 2156
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) FDLAB
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in hepatocellular carcinoma
    constitutional     --low  
    may contribute to Ca(2+) cycling perturbations manifest in the failing heart
    constitutional     --over  
    leads to a severe cardiac remodeling and arrhythmias
    tumoral     --over  
    highly overexpressed in pancreatic cancer
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS