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FLASH GENE
Symbol LRP4 contributors: mct/npt/pgu - updated : 12-01-2016
HGNC name low density lipoprotein receptor-related protein 4
HGNC id 6696
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • eight LDL-receptor class A domains
  • two calcium binding type EGF-like motif
  • twenty LDL-receptor class B repeats
  • a extracellular beta-propeller structured domain required for the sclerostin facilitator activity
  • an EGF-like motifs
  • a cytoplasmic domain having important signaling and/or anchoring functions in certain tissues but not at neuromuscular synapses
    • conjugated GlycoP
    isoforms Precursor a 17 aa signal peptide of 1.9 kda and a 1888 aa mature peptide of 210.1 kda
    HOMOLOGY
    interspecies homolog to rattus Lrp4 (96.4 pc)
    homolog to murine Lrp4 (96.6 pc)
    intraspecies homolog to low density lipoprotein receptor 4 (LDLR)
    Homologene
    FAMILY
  • LDLR family
    • CATEGORY receptor membrane
    SUBCELLULAR LOCALIZATION     plasma membrane
    text type II membrane anchored protein
    basic FUNCTION
  • acting as a potential cell surface endocytic receptor which binds and internalizes extracellular ligands for degradation by lysosomes
  • receptor for Agrin, which forms a complex with MUSK, and mediates MUSK activation by Agrin
  • can binds ligands that are structurally akin to AGRN and associates with other receptor tyrosine kinases, like MUSK, in these tissues
  • important for control and modification of Wnt signaling by its antagonistic effect on LRP6-mediated activation of WNT signaling
  • multi-functional receptor implicated in the regulation of several molecular pathways, including Wnt and Bmp signaling
  • specifically facilitates the previously described inhibitory action of sclerostin on WNT1/CTNNB signaling
  • functions as a direct muscle-derived retrograde signal for early steps in presynaptic differentiation
  • acts bi-directionally and coordinates synapse formation by binding Agrin, activating MUSK and stimulating postsynaptic differentiation
  • LRP4 and MUSK act as scaffolds for multiple binding partners, resulting in a complex and dynamic network of interacting proteins that is required for ACHR clustering
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS endocytosis transport
    PATHWAY
    metabolism
    signaling
    a component
  • LRP4 and MUSK can interact and form a complex
    • INTERACTION
    DNA
    RNA
    small molecule metal binding, nucleotide,
  • Ca2+
    • protein
  • AGRN receptor
  • sclerostin (SOST) interaction partner (interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone)
  • AGRN binds LRP4 and stimulates further MUSK phosphorylation, stabilizing nascent synapses
  • cis-acting ligand for MUSK, whereas AGRN functions as an allosteric and paracrine regulator to promote association between LRP4 and MUSK
  • interplay between LRP4 and SOSTDC1 in inhibiting Wnt/CTNNB1 signaling, providing an insight into how modulation of Wnt/CTNNB1 signaling controls cellular processes important for skin placode formation
  • ligand for MUSK, and binding affinity for MUSK is potentiated by agrin, a neuronally derived heparan-sulfate proteoglycan 9)
  • MESD binds to the intracellular form of LRP4 and promotes its glycosylation and cell-surface expression
  • COLQ binds directly to LRP4 but not to MUSK and COLQ interacts indirectly with MUSK through LRP4
  • LRP4 is a major receptor of COLQ
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) SDTY7 , SOST2 , CMS17
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    associated with bone overgrowth and impaired sclerostin facilitator function
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • polysyndactyly caused by two recessive mutations in the mouse Lrp4 gene
  • syndactyly caused by mutations in the bovine Lrp4 gene
  • Lrp4 mutant mice displayed a delay in placode initiation and changes in distribution and number of mammary precursor cells leading to abnormal morphology, number and position of mammary placodes
  • Lrp4(-/-) mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis
  • Lrp4 null mutations in mice result in limb development defects and in perinatal death due to a lack of neuromuscular junction formation