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FLASH GENE
Symbol PAFAH1B1 contributors: shn/mct - updated : 07-07-2015
HGNC name platelet-activating factor acetylhydrolase, isoform Ib, subunit 1 (45kDa)
HGNC id 8574
Corresponding disease
LIS1 lissencephaly 1
MDS Miller-Dieker lissencephaly syndrome
Location 17p13.3      Physical location : 2.496.922 - 2.588.908
Synonym name
  • platelet-activating factor acetylhydrolase, isoform Ib, alpha subunit (45kD)
  • Miller-Dieker syndrome chromosome region
  • platelet-activating factor acetylhydrolase, isoform Ib, alpha subunit (45kDa)
  • platelet-activating factor acetylhydrolase, isoform Ib, subunit 1 (45kDa)
  • platelet-activating factor acetylhydrolase IB subunit alpha
  • lissencephaly-1 protein
  • PAFAH alpha
  • PAF-AH alpha
  • PAF acetylhydrolase 45 kDa subunit
  • PAF-AH 45 kDa subunit
  • LIS-1
  • lissencephaly 1 protein
  • Synonym symbol(s) PAFAH, MDCR, PAFAHA, LIS2, LIS1, LIS-1
    EC.number 3.1.1.47
    DNA
    TYPE functioning gene
    SPECIAL FEATURE
    text processes two pseudogenes PAFAH1P1 and PAFAH1P2 mapping to 2p11.2 and 2q13, respectively
    STRUCTURE 91.99 kb     11 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - D17S831 - D17S1528 - LIS1 - D17S1798 - D17S1583 - cen
    Physical map
    SERPINF1 17p13.3 serine (or cysteine) proteinase inhibitor, clade F (alpha-2 antiplasmin, pigment epithelium derived factor), member 1 KIAA1936 17p13.3 KIAA1936 protein RPA1 17p13.3 replication protein A1, 70kDa NGRH2 LOC388319 17 LOC388319 DPH2L1 17p13.3 diptheria toxin resistance protein required for diphthamide biosynthesis-like 1 (S. cerevisiae) OVCA2 17p13.3 diptheria toxin resistance protein required for diphthamide biosynthesis-like 1 (S. cerevisiae) HIC1 17p13.3 hypermethylated in cancer 1 C17orf31 17p13.3 chromosome 17 open reading frame 31 SRR 17q13.3 serine racemase LOC388320 17 similar to Heterogeneous nuclear ribonucleoprotein A1 (Helix-destabilizing protein) (Single-strand binding protein) (hnRNP core protein A1) (HDP-1) (Topoisomerase-inhibitor suppressed) FLJ10534 17p13.3 hypothetical protein FLJ10534 KIAA0397 17p13.3 hypothetical protein FLJ10534 MNT 17p13.3 MAX binding protein MGC3329 17p13.3 hypothetical protein MGC3329 LOC390755 17 similar to eukaryotic translation initiation factor 4A1; initiation factor eIF-4A long form PAFAH1B1 17p13.3 platelet-activating factor acetylhydrolase, isoform Ib, alpha subunit 45kDa KIAA0664 17q13.3 platelet-activating factor acetylhydrolase, isoform Ib, alpha subunit 45kDa LOC388321 17 similar to Rap1 GTPase-activating protein 1 (Rap1GAP) OR1D5 17p13.3 olfactory receptor, family 1, subfamily D, member 5 OR1D2 17p13-p12 olfactory receptor, family 1, subfamily D, member 2 OR1E3P 17p13.3 olfactory receptor, family 1, subfamily E, member 3 pseudogene OR1G1 17p13.3 olfactory receptor, family 1, subfamily G, member 1 OR1P1P 17p13.3 olfactory receptor, family 1, subfamily P, member 1 pseudogene OR1A2 17p13.3 olfactory receptor, family 1, subfamily A, member 2 OR1A1 17p13.3 olfactory receptor, family 1, subfamily A, member 1 OR1D3P 17p13.3 olfactory receptor, family 1, subfamily D, member 3 pseudogene OR3A2 17p13.3 olfactory receptor, family 3, subfamily A, member 2 OR3A1 17p13.3 olfactory receptor, family 3, subfamily A, member 1 LOC390756 17 similar to Olfactory receptor 3A4 (Olfactory receptor 17-24) (OR17-24) LOC390757 17 similar to olfactory receptor MOR157-1 OR1E1 17p13.3 olfactory receptor, family 1, subfamily E, member 1 OR3A3 17p13.3 olfactory receptor, family 3, subfamily A, member 3 OR1E2 17p13.3 olfactory receptor, family 1, subfamily E, member 2 NYD-SP20 17p13.3 testes development-related NYD-SP20
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 - 5614 45 410 - 2011 21844209
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivepharynx   highly
    Nervousbrainforebraincerebral lobefrontalhighly
     brainforebraincerebral lobeoccipitalhighly
    Reproductivefemale systemuterus  highly
    Respiratoryrespiratory tractlarynx  highly
    cell lineage
    cell lines
    fluid/secretion plasma for the isoform 1b
    at STAGE
    physiological period embryo, fetal, pregnancy
    Text developing and fetal brain (migrating neurons)
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a LisH motif at the N terminus, forming a tightly associated homodimer with a four-helix antiparallel bundle core, while the parallel coiled-coil situated downstream is stabilized by three canonical heptad repeats
  • a putative microtubule associated protein binding domain
  • seven WD-40 repeats forming beta-propeller structure in the C terminus, phosphorylated on serine residues
  • conjugated PhosphoP
    mono polymer homomer , dimer
    HOMOLOGY
    interspecies ortholog to Pafah1b1, Mus musculus
    ortholog to Pafah1b1, Rattus norvegicus
    ortholog to PAFAH1B1, Pan troglodytes
    Homologene
    FAMILY
  • WD repeat LIS1/nudF family
  • CATEGORY enzyme , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
    intracellular,nucleus,chromatin/chromosome,kinetochore
    text
  • centriolar
  • associated to centrosome (connected to its role in neuronal migration, since the centrosome is believed to aid nuclear movement (nucleokinesis) as neurons move to its final destination in the cortex)
  • dynamically colocalizes with cytoplasmic dynein at centrosome, mitotic spindles, kinetochores, and cell cortex to execute various biological processes
  • colocalizes with cytoplasmic dynein and dynactin, predominantly in prometaphase kinetochores and at the cell cortex of dividing cells
  • in cytoplasm, localized to two punctate structures, one of which was located near the base of the flagella
  • basic FUNCTION
  • implicated in brain development, acts in several processes mediated by the dynein/dynactin pathway by interacting with dynein and other proteins
  • component of overlapping but distinct signal pathways including DCX that promotes neuronal migration
  • required for ordered neuronal migration in the cortex
  • playing a role in nuclear migration by interacting with multiple intracellular proteins and regulating cytoplasmic dynein function
  • playing a specific roles, with cytoplasmic dynein in radial migration and accumulate at the leading cell cortex of migrating fibroblasts
  • participates in a subset of dynein functions and may regulate the division of neuronal progenitor cells in the developing brain
  • regulating cytoplasmic dynein, as the motor responsible for centrosomal movement in neural precursor cells
  • playing an essential role for precise control of mitotic spindle orientation in both neuroepithelial stem cells and radial glial progenitor cells
  • function in microtubule capture and stabilization (may play a broader role throughout neural development in neuronal migration, neurite extension, and neuronal survival, besides its role neuroepithelial expansion and radial glial neurogenesis)
  • implicated in neuronal and non-neuronal migration and axon formation
  • suppresses the motility of cytoplasmic dynein on microtubules
  • mediating anterograde transport of cytoplasmic dynein to the plus end of cytoskeletal microtubules (MTs) as a dynein–PAFAH1B1 complex on transportable MTs
  • have important functions in the major migratory pathway in the developing forebrain
  • antagonistic effect of PAFAH1B2, PAFAH1B3 and NDEL1 for PAFAH1B1 binding, probably to modulate dynein functions
  • serves as a key regulator of the cytoplasmic dynein complex
  • inducing with NDE1 a persistent-force dynein state
  • functions as an intrinsic factor to control germline stem cell self-renewal, at least in part through regulating BMP signal transduction and E-cadherin–mediated cell adhesion
  • plays a potential tumor suppressor role in the development and progression of hepatocellular carcinoma
  • PAFAH Ib regulates endocytic membrane trafficking through novel mechanisms involving both PLA(2) activity and PAFAH1B1-dependent dynein function
  • important partner of the dynein/dynactin complex that plays several roles in the mitosis
  • essential for cortical microtubule organization and desmosome stability in the epidermis
  • association of PAFAH1B1 with outer arm dynein is modulated in response to alterations in flagellar motility
  • specific but cell type-restricted role for PAFAH1B1 in large vesicular transport
  • association of P with outer arm dynein is modulated in response to alterations in flagellar motility
  • operates like a “clutch” that prevents dynein's ATPase domain from transmitting a detachment signal to its track-binding domain
  • can convert dynein to a mechanochemical state in which its velocity is slowed and its microtubule attachments are prolonged
  • can generate mechanical diversity by regulating the structural changes that propagate through dynein's large motor domain
  • NDEL1, NUDCD3, PAFAH1B1 are critical components of cytoplasmic dynein complex
  • novel roles of PAFAH1B1, NDEL1 and NUDCD3 in the transport of mitochondria in axons
  • NDEL/NDE1 and PAFAH1B1 promote dynein and dynactin interaction in the context of spindle morphogenesis
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    text catalyzes the removal of the acetyl group at the SN-2 position of platelet-activating factor
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
    AFAH1B1 fatty acid and sterol
    a component
  • PAFAH1B catalytic subunit
  • dimerization is mediated by the N-terminal fragment and is essential for the protein biological function
  • dimerization is dependent on both the LisH motif and the residues downstream of it, including the first few turns of the helix (the coiled-coil does not contribute to dimerization, but instead is very labile and can adopt both supercoiled and helical conformations)
  • forms a complex with NUDCD2 and Hsp90
  • tetramer of two catalytic subunits, ALPHA1 (PAFAH1B3) and ALPHA2 (PAFAH1B2), and a regulatory dimer of LIS1 (PAFAH1B1)
  • molecular complex composed of NDE1, PAFAH1B1, and BRAP regulates the dynamic MAPK signaling threshold in a spatially dependent fashion
  • INTERACTION
    DNA
    RNA
    small molecule microtubules (
    protein
  • nuclear distribution gene C homolog (A. nidulans), NudC (
  • doublecortin, DCX (
  • mouse homolog of nuclear distribution gene E homolog 1 (A nidulans), mNudE (
  • nudE nuclear distribution gene E homolog (A. nidulans)-like 1, NUDEL (
  • dynactin, DCTN1 and dynein (
  • CAP-GLY domain containing linker protein 1, CLIP-170 (
  • reelin, RELN (
  • microtubule-associated protein 1B, MAP1B (
  • DAB1(partially pulled to a PAFAH1B1 -rich compartment)
  • fasciculation and elongation protein zeta-1 (FEZ1)
  • important for localization of its binding partners NDEL1, dynein, and CLIP1 (this localization is important for microtubule stability and capture at the cell cortex)
  • NDEL1 (PAFAH1B1 suppresses motility of microtubules (MTs) by cytoplasmic dynein in a reversible manner, whereas NDEL1 counteracts this suppressive effect)
  • HIV-1 Tat specific factor 1
  • LIS1 homodimer binds with either a homodimer of PAFAH1B2 or NUDEL to form a tetramer
  • regulatory subunit of PAFAH1B, that interacts with phosphoDAB1, an essential mediator of Reelin signaling
  • PAFAH1B3 and PAFAH1B2, were able to compete against NDEL1 and dynein for PAFAH1B1 binding in a dose-dependent manner (
  • recruitment factor for PAFAH1B1 (interactions between NDEL1 and its binding partners are positively regulated by phosphorylation of the unstructured C terminus)
  • PAFAH1B2 and PAFAH1B3 expression levels affect the distribution of endosomes within the cell through interactions with the dynein regulator PAFAH1B1
  • LIS1/dynactin plays the function in metaphase spindle assembly and mitotic checkpoint control
  • PDE4B and PDE4D
  • PAFAH1B1 is a strong dominant enhancer of ASUN and localization of PAFAH1B1 in male germ cells is ASUN dependent
  • BICD2, dynactin, and PAFAH1B1 cooperate in regulating dynein recruitment to cellular structures
  • can alter communication between dynein ATP hydrolyzing ring and its microtubule-binding stalk
  • during neuronal migration RELN interacts with PAFAH1B1 and induces nuclear translocation, accompanied by the ubiquitination of phosphorylated DAB1
  • cell & other
  • microtubule associated protein (directly or via an association with cytoplasmic dynein)
  • tubulin and microtubules (to suppress microtubule dynamics)
  • REGULATION
    Phosphorylated by protein kinase casein kinase II, CKII (
    Other regulated by NUDCD2 (NUDCD2 modulates the PAFAH1B1/dynein pathway by stabilizing PAFAH1B1 with Hsp90 chaperone)
    may be regulated by NUDC via Hsp90 chaperone
    ASSOCIATED DISORDERS
    corresponding disease(s) LIS1 , MDS
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in the brain tissue from schizophrenia
    constitutional     --over  
    in the developing brain results in brain abnormalities
    tumoral     --low  
    in hepatocellular carcinoma
    constitutional     --low  
    causes desmosomal defects, characterized by decreased levels of desmosomal components, decreased attachment of keratin filaments, and increased turnover of desmosomal proteins at the cell cortex
    constitutional     --other  
    defects in a PAFAH1B1/NdDEL1 regulatory switch could contribute to neurodegenerative diseases linked to axonal pathology in adults
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
  • calpain inhibition is a potential therapeutic intervention for lissencephaly caused by LIS mutations (
  • ANIMAL & CELL MODELS
  • Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal
  • Homozygous null mice die early in embryogenesis while mice with one inactive allele display cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway. Mice with further reduction of Pafah1b1 activity display more severe brain disorganization and cerebellar defects (
  • Homozygote mice deleted for the first coding exon are early lethal. Heterozygotes are viable and fertile but exhibite an aberrant morphology of cortical neurons and radial glia in the developing cortex and the neurons migrate more slowly (
  • Mutation in a C. elegans lis-1 allele (pnm-1) leads to convulsions mimicking epilepsy
  • neocortex of the Lis1-Nde1 double mutant mice showed over 80% reduction in surface area and inverted neuronal layers. Dramatically increased neuronal differentiation at the onset of corticogenesis in the mutant led to overproduction and abnormal development of earliest-born preplate neurons and Cajal-Retzius cells at the expense of progenitors (