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FLASH GENE
Symbol HSPA9 contributors: mct/ - updated : 21-04-2015
HGNC name heat shock 70kDa protein 9 (mortalin)
HGNC id 5244
Location 5q31.2      Physical location : 137.890.571 - 137.911.318
Genatlas name mortalin
Synonym name
  • peptide binding protein 74KDa
  • mortalin, perinuclear
  • p66-mortalin
  • stress-70 protein, mitochondrial
  • heat shock 70kDa protein 9 (mortalin-2)
  • 75 kDa glucose-regulated protein
    • Synonym symbol(s) MORT, MOT2, PBP74, HSPA9B, GRP75, GR75, CSA, MOT, MGC4500, MTHSP75, HSPA9B, mtHSP70
    DNA
    TYPE functioning gene
    STRUCTURE 20.09 kb     17 Exon(s)
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    17 - 3506 70 679 - 2000 10944461
    - splicing 1053 40 350 - 2009 19280369
    novel catecholamine binding function and this chaperone-like protein may be neuroprotective in dopamine-related central nervous system disorders
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
    Digestiveesophagus   highly
    Endocrineadrenal gland   highly
    Nervousbrain   highly Homo sapiens
    Reproductivefemale systembreastmammary gland highly
    Respiratorylung   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousglia Homo sapiens
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • 51-AAs N-terminal MTS sequence
    • HOMOLOGY
    interspecies homolog to murine mortalin 2
    intraspecies homolog to mitochondrial stress-70 protein
    Homologene
    FAMILY
  • heat shock protein 70 (HSP70) family
    • CATEGORY chaperone/stress , regulatory , transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,matrix
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic,vesicle
    text
  • not exclusively in mitochondria but also present in other organelles
  • found in multiple subcellular localizations such as the endoplasmic reticulum, cytoplasmic vesicles and the cytosol
  • majority of mortalin is located within the mitochondrial matrix (
    • basic FUNCTION
  • playing a role in the control of cell proliferation
  • implicated in the control of cell proliferation and cellular aging
  • controls centrosome duplication via modulating centrosomal localization of TP53
  • essential role in the differentiation of neuroblastoma (
  • plays a central role in mitochondrial biogenesis through its capacity to direct the import of nuclear-encoded proteins into the mitochondria
  • multifunctional protein that is capable of binding the neurotransmitter, dopamine, within the brain
  • plays an essential role in the regulation of dopamine-dependent behavior and plays an even greater role in the pathogenesis of schizophrenia
  • mitochondrial matrix chaperone, synthesized as a precursor protein which is cleaved into its mature form after import into mitochondria in a mitochondrial membrane potential-dependent manner
  • PINK1 and HSPA9 accumulated in different cellular compartments, and these two proteins share, at least partially, the same pathway of mitochondrial import
  • functional constituent of intracellular vesicles of a nonclathrin-, noncaveolin-dependent pathway that was sensitive to membrane cholesterol depletion
  • role of this mitochondrial chaperone in neurodegeneration and potential impaired mitochondrial protein quality control in Parkinson disease
  • plays an important role in the maintenance of mitochondrial homeostasis as critically related to neurodegeneration
  • may also act in signaling pathways responsible for mitochondrial stress response and the maintenance of mitochondrial integrity similar to that of the redox-sensing protein PARK7
  • crucial involvement of mortalin in the maintenance of mitochondrial morphology due to its function in the mitochondrial matrix
  • functions to maintain mitochondrial homeostasis and antagonize oxidative stress injury
  • plays an indispensible role in helping native protein refolding and importing proteins into the mitochondrial matrix
  • proposed function of HSPA9 and HSCB as the chaperone and co-chaperone, respectively, for human mitochondrial Fe-S cluster biosynthesis
  • HSPA9 facilitates BRAF-mutant tumor cell survival by suppressing SLC25A6-mediated mitochondrial membrane permeability
    • CELLULAR PROCESS cell life, proliferation/growth
    cell life, senescence
    nucleotide, transcription
    protein, post translation, folding
    PHYSIOLOGICAL PROCESS development
    text control of cell proliferation and cellular aging
    PATHWAY
    metabolism
    signaling
    a component
  • component of the chaperone GRP75/Mortalin/HSPA9B, a mitochondrial stress-induced peptide
  • functional constituent of noncaveolar, membrane raft-associated endocytic vesicles
  • HSPA9/PARK7 complex guards against mitochondrial oxidative stress and is indispensable for the maintenance of HSCs
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to TRA1
  • interacting HSPD1 through its N-terminal region (involvement in tumorigenesis, functional distinction in pathways involved in senescence)
  • cytosolic mortalin binds TP53 and by doing so, prevents translocation of the tumor suppressor into the nucleus
  • mitochondrial PARK7-interacting protein, also involved in the oxidative stress response
  • interacting with DNLZ (conserved histidine is critical for DNLZ regulation of mitochondrial HSPA9 catalytic activity)
  • interact with TP53 (both wild and mutant types) and inactivates its transcriptional activation and apoptotic functions in cancer cells
  • interacting with PARK2 (relatively decreased mortalin expression level and its impaired interaction with PARK2 could affect its roles in mitochondrial function)
  • interacts with fusion- and/or fission-related proteins and affects their mitochondrial location or translocation
  • HSPA9 was required for RARA/RXRA-mediated transcriptional regulation and was shown to reduce the proteasome-mediated degradation of RARA/RXRA in a RA-dependent manner
  • HSCB interacts with multiple proteins involved in ISC biogenesis including the ISCU ISC biogenesis complex and the HSPA9 ISC chaperone
  • binds preferentially to the D-state of ISCU and HSCB binds preferentially to the S-state of ISCU
  • activated the ATPase activity of HSPA9, and this activation was greatly increased by the addition of ISCU
  • CDKN1A has dual effects under HSPA9-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death
  • interaction between BCL2 and BL2L1 with a stress chaperone, mortalin (HSPA9)
  • ACSL5-induced mitochondrial HSPA9 expression is assumed to be a stress response to ACSL5-related changes in lipid metabolism and is regulated by the TP53 status
  • SLC25A6 is a previously unknown HSPA9 substrate and cell survival/death effector
    • cell & other
    REGULATION
    activated by HSCB
    Other differentially regulated in response to dopaminergic modulation
    ASSOCIATED DISORDERS
    corresponding disease(s)
    related resource MITOP database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    contributes significantly to tumorigenesis in breast carcinoma
    tumoral     --over  
    correlated with malignant transformation and poor cancer prognosis (
    constitutional     --low  
    in the mitochondrial fraction of neurons from the substantia nigra of Parkinson disease patients
    constitutional     --low  
    of HSPA8 and HSPA9 was observed in Alzheimer disease across the three brain regions compared to the controls, suggesting their participation in AD pathogenesis
    Susceptibility to Parkinson disease (PD)
    Variant & Polymorphism other
  • putative mutations in the mortalin, although rare, could contribute to the risk of developing PD
    • Candidate gene
    Marker
    Therapy target a good candidate target for cancer therapy
    SystemTypeDisorderPubmed
    cancerhemopathy 
    novel target for cancer adjuvant immunotherapy
    cancerdigestiveliver
    targeting HSPA9-TP53 interaction with either HSPA9 small hairpin RNA or a chemical or peptide inhibitor could induce p53-mediated tumor cell-specific apoptosis in hepatocellular carcinoma
    tumor  
    targeting HSPA9 has potential as a selective therapeutic strategy in B-Raf-mutant or MEK-ERK-driven tumors
    ANIMAL & CELL MODELS