Affinage

FEZ1

Fasciculation and elongation protein zeta-1 · UniProt Q99689

Length
392 aa
Mass
45.1 kDa
Annotated
2026-04-28
61 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FEZ1 is a kinesin-1 adaptor protein that functions as a central scaffold for microtubule-dependent axonal transport, neuronal polarity, dendrite development, and cell cycle regulation. FEZ1 forms an antiparallel homodimer that binds the kinesin heavy chain tail and links kinesin-1 to cargoes including mitochondria and presynaptic vesicle components, with phosphorylation by MARK/PAR-1 at Ser58 controlling cargo release and transport activation (PMID:12925768, PMID:17669366, PMID:27247180, PMID:24116125). Beyond transport, FEZ1 interacts with DISC1 to regulate dendritic growth of adult-born neurons, cooperates with CRMP1 and DCC/Syntaxin-1 to mediate Netrin-1 and Sema3A guidance responses, and its turnover is controlled by the Cdc20/APC ubiquitin ligase to modulate dendrite morphogenesis (PMID:22099459, PMID:33771901, PMID:24726361). FEZ1 also stabilizes Cdc25C to maintain Cdk1 activity during mitosis—loss of which causes accelerated mitotic progression and cancer susceptibility in mice—and serves as an innate restriction factor against HIV-1 by engaging the capsid hexamer central pore to direct kinesin-1-dependent nuclear trafficking of viral particles (PMID:17349584, PMID:31422020, PMID:25818806).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    The foundational question of what role UNC-76/FEZ1 plays in nervous system development was answered: loss of UNC-76 in C. elegans disrupts axon bundling and elongation, and human FEZ1 can rescue this defect, establishing an evolutionarily conserved neuronal function.

    Evidence Genetic loss-of-function in C. elegans with cross-species complementation by human FEZ1

    PMID:9096408

    Open questions at the time
    • Molecular mechanism of action unknown
    • Binding partners unidentified
    • Whether function is cell-autonomous not established
  2. 1999 High

    Identification of PKCζ as a FEZ1 kinase and interactor established that FEZ1 is a phosphorylation-regulated signaling effector, with PKCζ-dependent phosphorylation controlling FEZ1 subcellular localization and promoting neuronal differentiation.

    Evidence Yeast two-hybrid, co-expression/localization in COS-7 cells, PC12 differentiation assay

    PMID:9971736

    Open questions at the time
    • Phosphorylation sites not mapped
    • Whether PKCζ regulation occurs in vivo unknown
    • Downstream effectors of the FEZ1-PKCζ axis not identified
  3. 2001 High

    A parallel function for FEZ1/LZTS1 in cell cycle control was revealed: FEZ1 interacts with Cdk1 at G2/M and its re-expression in cancer cells suppresses tumorigenicity with S-G2/M accumulation, linking FEZ1 to mitotic regulation independently of its neuronal roles.

    Evidence Co-immunoprecipitation with p34(cdc2), cell cycle analysis, stable re-expression in cancer cells

    PMID:11504921

    Open questions at the time
    • Mechanism by which FEZ1 affects Cdk1 activity not defined
    • Relevance of PKA hyperphosphorylation to mitotic function unclear
  4. 2003 High

    The critical mechanistic question of how FEZ1 exerts its axonal transport function was answered: Drosophila UNC-76 directly binds kinesin heavy chain and shows dosage-sensitive genetic interactions with kinesin components, placing FEZ1 as a bona fide kinesin-1 adaptor.

    Evidence Yeast two-hybrid, copurification, Drosophila genetic epistasis with Khc and Klc

    PMID:12925768

    Open questions at the time
    • Cargo identity unknown
    • Whether mammalian FEZ1 binds KHC directly not yet shown
    • Regulation of the FEZ1-kinesin interaction uncharacterized
  5. 2004 High

    Discovery of non-proteolytic K27-linked ubiquitylation of FEZ1 by the E4B/UFD2a ubiquitin ligase, enhanced by PKCζ, revealed a non-degradative post-translational modification required for neuritogenesis.

    Evidence Yeast two-hybrid, Co-IP, in vitro ubiquitylation assay, dominant-negative E4B in PC12 cells

    PMID:15466860

    Open questions at the time
    • Functional consequence of K27-linked ubiquitin chains on FEZ1 unknown
    • Whether ubiquitylation regulates kinesin binding not tested
  6. 2005 High

    Two independent studies revealed that FEZ1 restricts viral infection: it blocks retroviral nuclear entry (HIV-1) and modulates JC virus protein expression/trafficking, while JC virus agnoprotein dissociates FEZ1 from microtubules, establishing FEZ1 as a host factor at the virus-cytoskeleton interface.

    Evidence Overexpression/RNAi with retroviral infection assays; yeast two-hybrid and microtubule cosedimentation with JCV agnoprotein

    PMID:15843383 PMID:15879557

    Open questions at the time
    • Mechanism of HIV-1 nuclear entry block not defined
    • Whether antiviral activity relates to kinesin adaptor function unknown
  7. 2006 Medium

    FEZ1 was placed upstream of neuronal polarity and organelle transport: RNAi in primary hippocampal neurons showed that FEZ1 is required for axon formation and anterograde mitochondrial motility, while interaction with SCOC/UNC-69 defined a conserved adaptor pair for axon extension and synaptogenesis.

    Evidence RNAi in primary hippocampal neurons with live mitochondrial imaging; yeast two-hybrid and genetic interaction in C. elegans for SCOC/UNC-69

    PMID:16725058 PMID:17173861

    Open questions at the time
    • Whether FEZ1-SCOC interaction is required for mitochondrial transport not tested
    • Cargo selectivity mechanism unknown
  8. 2007 High

    Two key advances defined the FEZ1-kinesin-1-mitochondria transport pathway in mammalian neurons and established FEZ1/LZTS1 as a mitotic checkpoint regulator: FEZ1 co-immunoprecipitates with KIF5 and tubulin and its depletion blocks anterograde mitochondrial transport; separately, Lzts1-knockout mice revealed that FEZ1 stabilizes Cdc25C to maintain Cdk1 activity during mitosis, with loss causing cancer susceptibility.

    Evidence Co-IP/pulldown in PC12 cells with RNAi and live imaging; Lzts1 knockout mice with MEF cell cycle and Cdk1/Cdc25C biochemical analysis

    PMID:17349584 PMID:17669366

    Open questions at the time
    • How FEZ1 stabilizes Cdc25C molecularly not defined
    • Whether transport and cell cycle functions are mutually exclusive or context-dependent
  9. 2009 High

    Biophysical characterization established that FEZ1 is a natively unfolded elongated dimer whose C-terminal phosphorylation by PKC inhibits specific protein interactions, and endogenous neuronal FEZ1 was confirmed as a physiological restriction factor for HIV-1 in human brain cells.

    Evidence SAXS, CD, and in vitro phosphorylation/pulldown; siRNA/overexpression in primary human neurons and microglia with HIV-1 infection assay

    PMID:18615714 PMID:19667186

    Open questions at the time
    • Atomic-resolution structure of full-length FEZ1 lacking
    • Which PKC isoform is physiologically relevant in neurons unclear
  10. 2013 High

    Structural studies of the FEZ1-SCOC complex resolved the interaction architecture: NMR showed FEZ1 coiled-coil dimerizes in antiparallel orientation, and crystallography/cross-linking defined a heterotetrameric FEZ1-SCOC complex model for the kinesin adaptor machinery.

    Evidence X-ray crystallography of SCOC coiled-coil, NMR of FEZ1(92-194), SAXS, MS-based cross-linking, mutagenesis

    PMID:24098481 PMID:24116125

    Open questions at the time
    • No structure of the full FEZ1-SCOC-kinesin ternary complex
    • How heterotetrameric assembly regulates cargo binding unknown
  11. 2014 High

    FEZ1 protein turnover was placed under control of the Cdc20/APC ubiquitin ligase, with BubR1 acetylation modulating Cdc20/APC activity upstream; this defined FEZ1 degradation as a regulatory node for dendrite growth in adult-born neurons.

    Evidence Genetic knockdown/overexpression epistasis in hippocampal dentate granule cells and olfactory neurons, protein degradation assays

    PMID:24726361

    Open questions at the time
    • Ubiquitylation sites on FEZ1 for Cdc20/APC not mapped
    • Relationship between Cdc20/APC-mediated degradation and E4B-mediated non-proteolytic ubiquitylation unclear
  12. 2015 High

    The mechanism by which HIV-1 exploits FEZ1 was resolved: HIV-1 capsids associate with FEZ1 to engage kinesin-1 for directed nuclear trafficking, and FEZ1 depletion abolishes net inward movement of viral particles, establishing FEZ1 as the host adaptor hijacked by HIV-1 for cytoplasmic transport.

    Evidence RNAi, live-cell single-particle tracking, dominant-negative FEZ1 kinesin-binding mutants, infectivity assays

    PMID:25818806

    Open questions at the time
    • Direct FEZ1-capsid binding interface not structurally defined at this point
    • Whether other retroviruses use the same mechanism unknown
  13. 2016 High

    MARK/PAR-1 kinases were identified as physiological regulators of FEZ1 via Ser58 phosphorylation: loss of phosphorylation causes pathological co-aggregation of FEZ1, kinesin-1, and presynaptic cargoes in axons, with similar aggregates found in Alzheimer's disease model brains.

    Evidence MS-based phosphosite identification, Drosophila and mouse genetic mutants, axonal transport assays, AD model brain immunofluorescence

    PMID:27247180

    Open questions at the time
    • Whether Ser58 phosphorylation directly regulates kinesin binding or cargo release not biochemically dissected
    • Causal role in Alzheimer's pathogenesis not established
  14. 2019 High

    The molecular basis of FEZ1-HIV-1 capsid recognition was defined: FEZ1's acidic poly-glutamate stretches bind the positively charged central pore of CA hexamers, competing with IP6/nucleotides, and mutation of these residues reduces viral nuclear trafficking and infection.

    Evidence Biochemical binding assays, structure-function mutagenesis, all-atom MD simulations, single-particle tracking

    PMID:31422020

    Open questions at the time
    • No experimental co-structure of FEZ1-CA hexamer
    • Whether this interaction is targetable therapeutically not tested
  15. 2021 High

    FEZ1 was integrated into axon guidance signaling: it forms complexes with CRMP1 at growth cones and with DCC/Syntaxin-1 in the Netrin-1 pathway, and its loss abolishes growth cone responses to both Netrin-1 and Sema3A, while CRISPR deletion in human motor neurons confirmed an essential role in axon/dendrite development and synaptic protein transport.

    Evidence Co-IP and siRNA in primary hippocampal neurons with guidance cue assays; CRISPR KO in human ESC-derived motor neurons; Drosophila rescue with rapamycin/metformin

    PMID:33395696 PMID:33771901

    Open questions at the time
    • How FEZ1 connects kinesin-1 transport to guidance receptor signaling mechanistically unresolved
    • Whether UNC-51/ATG1 directly phosphorylates FEZ1 in mammalian neurons not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of full-length FEZ1 and its ternary complexes with kinesin-1 and cargoes, the mechanism by which FEZ1 stabilizes Cdc25C, the interplay between its multiple phosphorylation events (PKCζ, MARK/PAR-1, PKA, UNC-51) in determining cargo selectivity, and whether its transport and cell-cycle functions are mechanistically linked or represent context-dependent moonlighting.
  • No full-length atomic structure
  • Cargo selectivity mechanism undefined
  • Integration of multiple kinase inputs not systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-9609507 Protein localization 5 R-HSA-112316 Neuronal System 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 1
Partners
CLASP2CRMP1DCCDISC1KIF5BPRKCZSCOCUBE4B
Complex memberships
FEZ1-SCOC heterotetramerFEZ1-kinesin-1 transport complexFEZ1/SCOC/ULK1/NBR1 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 UNC-76 (FEZ1 ortholog in C. elegans) is necessary for normal axonal bundling and elongation within axon bundles; the protein is found in cell bodies and processes of all neurons throughout development, suggesting a structural role in axonal bundle formation or transduction of signals to the intracellular machinery regulating axonal extension. At least one human homolog can functionally complement UNC-76 in C. elegans. Genetic loss-of-function analysis in C. elegans; cross-species complementation assay Proceedings of the National Academy of Sciences of the United States of America High 9096408
1999 FEZ1 (mammalian UNC-76 ortholog) interacts with the regulatory (V1) domain of PKCζ and weakly with PKCε via yeast two-hybrid; in COS-7 cells co-expressing FEZ1 and PKCζ, FEZ1 is phosphorylated by PKCζ and localizes to the plasma membrane when PKCζ is inactive but translocates to the cytoplasm when constitutively active PKCζ is expressed. Co-expression of FEZ1 and constitutively active PKCζ stimulates neuronal differentiation of PC12 cells. Yeast two-hybrid screening, co-expression in COS-7 cells, subcellular localization, PC12 differentiation assay The Journal of cell biology High 9971736
2001 FEZ1/LZTS1 introduction into FEZ1-negative cancer cells suppresses tumorigenicity and reduces cell growth with accumulation at late S-G2/M. Fez1/Lzts1 protein is hyperphosphorylated by cAMP-dependent kinase (PKA) during cell-cycle progression and interacts with p34(cdc2) at late S-G2/M stage in vivo, linking FEZ1 to mitotic regulation. Stable re-expression in cancer cells, co-immunoprecipitation, cell cycle analysis, phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America High 11504921
2003 Drosophila UNC-76 (FEZ1 ortholog) binds to the tail domain of kinesin heavy chain (KHC) in yeast two-hybrid and copurification assays, forming a stable complex in vivo. Loss of Unc-76 in Drosophila causes locomotion and axonal transport defects similar to kinesin mutants, and Unc-76 shows dosage-sensitive genetic interactions with Khc and Kinesin light chain mutations, placing UNC-76/FEZ1 in the kinesin-1 axonal transport pathway. Yeast two-hybrid, copurification, Drosophila genetics (dosage-sensitive interactions, loss-of-function) Molecular biology of the cell High 12925768
2004 E4B (UFD2a), a U-box-type ubiquitin ligase (E3/E4), interacts with FEZ1 (identified by yeast two-hybrid), and this interaction is enhanced by constitutively active PKCζ. E4B mediates K27-linked polyubiquitylation of FEZ1 without destabilizing it (non-proteolytic). Dominant-negative E4B inhibits NGF-induced neurite extension and FEZ1/PKCζ-driven neuritogenesis in PC12 cells. Yeast two-hybrid, co-immunoprecipitation, ubiquitylation assay, dominant-negative expression in PC12 cells The Journal of biological chemistry High 15466860
2005 FEZ1 interacts directly with JC virus agnoprotein (yeast two-hybrid, in vitro binding assay) and with microtubules (cosedimentation assay). Agnoprotein induces dissociation of FEZ1 from microtubules, inhibits FEZ1-promoted neurite outgrowth in PC12 cells, and overexpression of FEZ1 suppresses JCV protein expression and intracellular trafficking. Yeast two-hybrid, in vitro binding assay, microtubule cosedimentation assay, PC12 neurite outgrowth assay The Journal of biological chemistry High 15843383
2005 FEZ1 overexpression in Rat2 fibroblasts and 293T cells confers potent resistance to retroviral infection by blocking nuclear entry of viral DNA (after reverse transcription but before nuclear import). RNAi knockdown of FEZ1 in a resistant cell line partially restores infectivity, demonstrating that endogenous FEZ1 contributes to the post-entry block. Overexpression and RNAi in cell lines, retroviral infection assay, viral DNA quantification Genes & development High 15879557
2006 FEZ1 dimerizes via its C-terminal coiled-coil region and heterodimerizes with FEZ2 through the same region. Yeast two-hybrid screening of human fetal brain cDNA identified 16 interacting proteins; in vitro pull-down confirmed interactions with FEZ1 itself, SAP30L, DRAP1, and BAF60a (transcription regulatory proteins), suggesting a role in transcriptional control in addition to transport. Yeast two-hybrid, in vitro pull-down with recombinant proteins, deletion mapping The Journal of biological chemistry Medium 16484223
2006 FEZ1 RNAi in rat embryo hippocampal neurons represses axon formation and retards anterograde mitochondrial movement in neurites, and causes mitochondrial elongation, establishing a role for FEZ1 in neuronal polarity by controlling mitochondrial motility. RNAi in primary hippocampal neurons, live imaging of mitochondrial transport Biochemical and biophysical research communications Medium 17173861
2006 UNC-69 (SCOCO ortholog) physically interacts with UNC-76 (FEZ1 ortholog) in C. elegans; they colocalize as puncta in neuronal processes and cooperate to regulate axon extension and synapse formation. Chicken UNC-69 knockdown causes axon guidance defects. Yeast two-hybrid, genetic interaction analysis in C. elegans, RNAi in chicken Journal of biology Medium 16725058
2007 FEZ1 associates with kinesin-5 (KIF5) and tubulin as shown by immunoprecipitation and pulldown assay in NGF-stimulated PC12 cells. FEZ1 co-localizes with mitochondria in neurites and RNAi silencing of FEZ1 reduces anterograde mitochondrial motility, indicating that the FEZ1/kinesin complex transports mitochondria along microtubules into extending neurites. Immunoprecipitation, pulldown assay, RNAi, live imaging of mitochondrial transport in PC12 cells Biochemical and biophysical research communications High 17669366
2007 Lzts1 knockout mice show increased Cdc25C degradation during M phase resulting in decreased Cdk1 activity, accelerated mitotic progression, resistance to taxol- and nocodazole-induced M phase arrest, and improper chromosome segregation. This defines FEZ1/LZTS1 as a regulator of the Cdk1/Cdc25C axis in mitosis and shows that Fez1 deficiency predisposes mice to spontaneous and carcinogen-induced cancers. Knockout mouse model, MEF cell cycle analysis, biochemical assays for Cdc25C and Cdk1 activity Cancer cell High 17349584
2008 Fez1-knockout mice show hyperactivity and enhanced responses to MK-801 and methamphetamine. In vivo microdialysis reveals exaggerated methamphetamine-induced dopamine release in the nucleus accumbens, implicating FEZ1 in mesolimbic dopaminergic transmission. Immunofluorescence shows FEZ1 is predominantly located in GABAergic interneurons. Knockout mouse model, behavioral testing, in vivo microdialysis, immunofluorescence Human molecular genetics High 18647754
2009 Human FEZ1 is a natively unfolded protein that forms a dimer of elongated shape; SAXS experiments establish the overall structure. In vitro pulldown confirms N-terminal dimerization. In vitro phosphorylation by PKC occurs mainly in the C-terminal region and inhibits FEZ1 interaction with the CLASP2-interacting domain, suggesting phosphorylation-dependent regulation of cargo binding. SAXS, circular dichroism, fluorescence spectroscopy, limited proteolysis, in vitro pulldown, in vitro phosphorylation assay Proteins High 18615714
2009 Among human brain cells, neurons naturally express high levels of FEZ1 and are correspondingly less susceptible to pseudotyped HIV-1 infection. siRNA knockdown of endogenous FEZ1 in neurons increases HIV-1 infectivity, while FEZ1 overexpression in microglia increases resistance, establishing endogenous FEZ1 as a neuron-specific determinant of HIV-1 resistance. siRNA knockdown and overexpression in primary brain cells, pseudotyped HIV-1 infection assay, Western blot Proceedings of the National Academy of Sciences of the United States of America High 19667186
2009 FEZ1 interacts with CLASP2 and NEK1 through coiled-coil interactions in vitro; all three proteins colocalize with gamma-tubulin in a perinuclear/centrosomal region. CLASP2 is phosphorylated by active PKC isoforms and FEZ1/CLASP2 colocalization is inhibited by PMA treatment, suggesting PKC-regulated centrosomal function. In vitro pull-down, immunofluorescence colocalization, PMA treatment Molecular and cellular biochemistry Medium 19924516
2010 FEZ1 forms a disulfide bond-mediated dimer through Cys-133; this was demonstrated in vitro with the fragment FEZ1(92-194), full-length His-FEZ1, and endogenous FEZ1 from HEK293 cells. The disulfide bond is proposed to enable FEZ1 to function as a bivalent transport adaptor capable of simultaneously binding two cargoes. In vitro biochemical assays, endogenous protein analysis from HEK293 cells, mass spectrometry Journal of proteome research Medium 20812761
2011 FEZ1 interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus. This interaction defines a DISC1-FEZ1 pathway for dendritic development distinct from a parallel DISC1-NDEL1 pathway that regulates cell positioning. In vivo retroviral-mediated gene manipulation in adult mouse hippocampus, genetic epistasis, morphological analysis of newborn neurons Neuron High 22099459
2013 Crystal structure of the SCOC coiled-coil domain (2.7 Å) shows a parallel left-handed coiled-coil dimer. SCOC forms a stable homogeneous complex with the coiled-coil domain of FEZ1; SCOC dimerization and surface residue R117 are important for the SCOC-FEZ1 interaction. X-ray crystallography, multi-angle laser light scattering, native mass spectrometry, mutagenesis PloS one High 24098481
2013 NMR studies establish that FEZ1(92-194) homodimerizes in antiparallel topology. SAXS and MS-based cross-linking define the FEZ1-SCOC interaction interface, consistent with the UNC-76/UNC-69 interface, and support a heterotetrameric FEZ1/SCOC complex model for the kinesin adaptor transport machinery. NMR, SAXS, cross-linking coupled with mass spectrometry, molecular modelling PloS one High 24116125
2014 Cdc20/APC ubiquitin ligase complex controls dendrite growth in neurons by regulating FEZ1 protein degradation. BubR1 modulates this pathway upstream of Cdc20/APC, and BubR1 function is dependent on its acetylation status; Hdac11 deacetylates BubR1 to disinhibit Cdc20/APC. This places FEZ1 as a downstream substrate of the Cdc20/APC-BubR1-Hdac11 axis in dendrite development. Genetic manipulation (knockdown/overexpression) in hippocampal dentate granule cells and olfactory bulb neurons, protein degradation assay, epistasis analysis Cell reports High 24726361
2015 HIV-1 capsids associate with FEZ1 (kinesin-1 adaptor) for inward movement toward the nucleus. RNAi depletion of FEZ1 causes HIV-1 particles to exhibit bi-directional but no net nuclear movement. Both dynein and kinesin-1 are required for nuclear trafficking, and exogenously expressed FEZ1 must bind kinesin-1 to promote early HIV-1 infection, establishing FEZ1 as a host regulator of HIV-1 nuclear trafficking. RNAi depletion, live-cell single-particle tracking, dominant-negative FEZ1 mutants, infectivity assays Nature communications High 25818806
2016 FEZ1 cargoes are enriched for presynaptic components. MARK/PAR-1 kinases phosphorylate FEZ1 at serine 58, and loss of MARK/PAR-1 impairs axonal transport causing FEZ1, kinesin-1, and cargoes to co-aggregate in cell bodies and axons. Presynaptic specializations are markedly reduced in FEZ1 and MARK/PAR-1 mutants. Abnormal co-aggregates of unphosphorylated FEZ1, kinesin-1, and putative cargoes are found in Alzheimer's disease model mouse brains. Mass spectrometry for phosphosite identification, genetic mutants (Drosophila and mouse), immunofluorescence, transport assays Scientific reports High 27247180
2018 UNC-76/FEZ1 (C. elegans) mutants show increased mitochondrial density in touch receptor neuron processes with elevated Kinesin Heavy and Light Chain levels in neurons and net anterograde bias in mitochondrial flux. Genetic analyses indicate that increased mitochondrial density in unc-76 depends partly on Dynein, establishing FEZ1 as a regulator of the anterograde/retrograde balance of mitochondrial axonal transport. C. elegans genetics, mitochondrial density quantification, flux analysis, genetic epistasis with dynein mutants Scientific reports Medium 29895958
2019 FEZ1 directly interacts with HIV-1 capsid protein (CA) hexamers through multiple acidic poly-glutamate stretches that bind the positively charged central pore of CA hexamers, competing with nucleotides and IP6 at the same site. All-atom MD simulations define the molecular details. Mutation of FEZ1 capsid-interacting residues significantly reduces nuclear trafficking of HIV-1 and early infection. Biochemical binding assays, structure-function mutagenesis, all-atom molecular dynamics simulations, single-particle trafficking assay, infectivity assay Cell reports High 31422020
2021 FEZ1 forms a complex with CRMP1 at neuronal growth cones; FEZ1 deficiency causes growth cone collapse and impaired axonal development similar to CRMP1 loss-of-function. FEZ1 also forms a separate complex with DCC and Syntaxin-1 (Netrin-1 signaling components); FEZ1-deficient neurons fail to respond to Netrin-1 (axon) or Sema3A (dendrite) guidance cues. Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown in primary hippocampal neurons, guidance cue treatment assays eNeuro Medium 33771901
2021 FEZ1 deletion in human motor neurons derived from embryonic stem cells strongly impairs axon and dendrite development and significantly delays synaptic protein transport into developing neurites. In Drosophila unc-76 mutants, severe locomotion impairments and reduction of synaptic boutons at neuromuscular junctions occur, and these are ameliorated by pharmacological activation of UNC-51/ATG1 (a FEZ1-activating kinase) with rapamycin and metformin. CRISPR deletion in human ESC-derived motor neurons, Drosophila genetics, pharmacological rescue, synaptic bouton quantification Human molecular genetics High 33395696
2017 FEZ1 interacts with retinoic acid receptor (RAR) through FEZ1's coiled-coil region and RAR's ligand-binding domain (in vitro binding). In the presence of retinoic acid, FEZ1 specifically induces Hoxb4 gene expression from an 86-gene panel, placing FEZ1 as a co-regulator in RAR-dependent transcription. In vitro binding experiments, domain mapping, gene expression panel in cellular assay FEBS open bio Medium 29321952
2022 SCOC, ULK1, and NBR1 directly bind FEZ1 protein (demonstrated by immunoprecipitation), forming a FEZ1/SCOC/ULK1/NBR1 complex implicated in autophagy regulation in neuronal cells. Immunoprecipitation, dual-luciferase reporter assay (for miR-129-5p targeting) Bioengineered Medium 35435132

Source papers

Stage 0 corpus · 61 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation. Proceedings of the National Academy of Sciences of the United States of America 150 9096408
1999 The FEZ1 gene at chromosome 8p22 encodes a leucine-zipper protein, and its expression is altered in multiple human tumors. Proceedings of the National Academy of Sciences of the United States of America 138 10097140
2015 HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus. Nature communications 112 25818806
2003 Three-dimensional structure of FEZ-1, a monomeric subclass B3 metallo-beta-lactamase from Fluoribacter gormanii, in native form and in complex with D-captopril. Journal of molecular biology 110 12507470
2001 FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis. Proceedings of the National Academy of Sciences of the United States of America 92 11504921
2011 Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia. Neuron 85 22099459
1999 Mammalian homologue of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein. The Journal of cell biology 85 9971736
2003 The kinesin-associated protein UNC-76 is required for axonal transport in the Drosophila nervous system. Molecular biology of the cell 76 12925768
2004 Association analysis of FEZ1 variants with schizophrenia in Japanese cohorts. Biological psychiatry 66 15522253
2019 FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking. Cell reports 63 31422020
2005 Identification of FEZ1 as a protein that interacts with JC virus agnoprotein and microtubules: role of agnoprotein-induced dissociation of FEZ1 from microtubules in viral propagation. The Journal of biological chemistry 60 15843383
2007 Fez1/Lzts1 absence impairs Cdk1/Cdc25C interaction during mitosis and predisposes mice to cancer development. Cancer cell 58 17349584
2001 Biochemical characterization of the FEZ-1 metallo-beta-lactamase of Legionella gormanii ATCC 33297T produced in Escherichia coli. Antimicrobial agents and chemotherapy 58 11257043
2007 Axonal guidance protein FEZ1 associates with tubulin and kinesin motor protein to transport mitochondria in neurites of NGF-stimulated PC12 cells. Biochemical and biophysical research communications 57 17669366
2006 Fasciculation and elongation protein zeta-1 (FEZ1) participates in the polarization of hippocampal neuron by controlling the mitochondrial motility. Biochemical and biophysical research communications 55 17173861
2008 Mice lacking the schizophrenia-associated protein FEZ1 manifest hyperactivity and enhanced responsiveness to psychostimulants. Human molecular genetics 53 18647754
2004 Functional regulation of FEZ1 by the U-box-type ubiquitin ligase E4B contributes to neuritogenesis. The Journal of biological chemistry 51 15466860
2001 Fez1/lzts1 alterations in gastric carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 47 11410489
2004 Fez1 is layer-specifically expressed in the adult mouse neocortex. The European journal of neuroscience 45 15579145
2002 FEZ1/LZTS1 is down-regulated in high-grade bladder cancer, and its restoration suppresses tumorigenicity in transitional cell carcinoma cells. The American journal of pathology 44 11943719
2002 NBR1 interacts with fasciculation and elongation protein zeta-1 (FEZ1) and calcium and integrin binding protein (CIB) and shows developmentally restricted expression in the neural tube. European journal of biochemistry 43 11856312
2006 FEZ1 dimerization and interaction with transcription regulatory proteins involves its coiled-coil region. The Journal of biological chemistry 39 16484223
2004 Expression of fasciculation and elongation protein zeta-1 (FEZ1) in the developing rat brain. Brain research. Molecular brain research 38 14992819
2005 Reduced FEZ1/LZTS1 expression and outcome prediction in lung cancer. Cancer research 37 15735004
2014 Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system. Cell reports 34 24726361
2008 Down-regulation of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma involves promoter methylation and associates with metastasis. Breast cancer research and treatment 34 18686028
2006 The short coiled-coil domain-containing protein UNC-69 cooperates with UNC-76 to regulate axonal outgrowth and normal presynaptic organization in Caenorhabditis elegans. Journal of biology 31 16725058
2002 Differential expression of FEZ1/LZTS1 gene in lung cancers and their cell cultures. Clinical cancer research : an official journal of the American Association for Cancer Research 31 12114433
2009 Human FEZ1 has characteristics of a natively unfolded protein and dimerizes in solution. Proteins 30 18615714
2018 UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport. Scientific reports 28 29895958
2005 Overexpression of fasciculation and elongation protein zeta-1 (FEZ1) induces a post-entry block to retroviruses in cultured cells. Genes & development 28 15879557
2016 Phosphorylation of FEZ1 by Microtubule Affinity Regulating Kinases regulates its function in presynaptic protein trafficking. Scientific reports 26 27247180
2004 Probing the specificity of the subclass B3 FEZ-1 metallo-beta-lactamase by site-directed mutagenesis. The Journal of biological chemistry 26 15159411
2003 Down-regulation of FEZ1/LZTS1 gene with frequent loss of heterozygosity in oral squamous cell carcinomas. International journal of oncology 26 12851677
2009 The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection. Proceedings of the National Academy of Sciences of the United States of America 20 19667186
2017 Disruption to schizophrenia-associated gene Fez1 in the hippocampus of HDAC11 knockout mice. Scientific reports 18 28928414
2017 Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development. Translational psychiatry 18 29249816
2007 Fez1/Lzts1 a new mitotic regulator implicated in cancer development. Cell division 18 17718912
2006 The FEZ1 gene shows no association to schizophrenia in Caucasian or African American populations. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 17 16936715
2010 Functions of fasciculation and elongation protein zeta-1 (FEZ1) in the brain. TheScientificWorldJournal 16 20730382
2010 Human FEZ1 protein forms a disulfide bond mediated dimer: implications for cargo transport. Journal of proteome research 16 20812761
2008 Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis. Carcinogenesis 16 18192690
2008 Over-expression of GFP-FEZ1 causes generation of multi-lobulated nuclei mediated by microtubules in HEK293 cells. Experimental cell research 16 18439996
2007 Failure to confirm the association between the FEZ1 gene and schizophrenia in a Japanese population. Neuroscience letters 16 17374448
2009 FEZ1 interacts with CLASP2 and NEK1 through coiled-coil regions and their cellular colocalization suggests centrosomal functions and regulation by PKC. Molecular and cellular biochemistry 15 19924516
2011 Four mood stabilizers commonly induce FEZ1 expression in human astrocytes. Bipolar disorders 14 22017218
2021 FEZ1 Forms Complexes with CRMP1 and DCC to Regulate Axon and Dendrite Development. eNeuro 13 33771901
2011 FEZ2 has acquired additional protein interaction partners relative to FEZ1: functional and evolutionary implications. PloS one 13 21408165
2014 Fasciculation and elongation protein zeta-1 (FEZ1) expression in reactive astrocytes in a rat model of Parkinson's disease. Neuropathology and applied neurobiology 11 23888906
2022 miR-129-5p targets FEZ1/SCOC/ULK1/NBR1 complex to restore neuronal function in mice with post-stroke depression. Bioengineered 10 35435132
2013 Crystal structure of the human short coiled coil protein and insights into SCOC-FEZ1 complex formation. PloS one 10 24098481
2009 Expression of fasciculation and elongation protein zeta-1 (FEZ1) in cultured rat neonatal astrocytes. Molecular and cellular biochemistry 10 19199094
2021 Loss of FEZ1, a gene deleted in Jacobsen syndrome, causes locomotion defects and early mortality by impairing motor neuron development. Human molecular genetics 8 33395696
2018 Methylphenidate and Guanfacine Ameliorate ADHD-Like Phenotypes in Fez1-Deficient Mice. Molecular neuropsychiatry 8 29888233
2019 Is there a new pathway relationship between melatonin and FEZ1 in experimental rat model of Alzheimer's disease? Bratislavske lekarske listy 7 30685996
2023 Single-cell transcriptomics implicates the FEZ1-DKK1 axis in the regulation of corneal epithelial cell proliferation and senescence. Cell proliferation 6 36851859
2023 FEZ1 participates in human embryonic brain development by modulating neuronal progenitor subpopulation specification and migrations. iScience 6 38213789
2017 Fasciculation and elongation zeta-1 protein (FEZ1) interacts with the retinoic acid receptor and participates in transcriptional regulation of the Hoxb4 gene. FEBS open bio 6 29321952
2013 Structural analysis of intermolecular interactions in the kinesin adaptor complex fasciculation and elongation protein zeta 1/ short coiled-coil protein (FEZ1/SCOCO). PloS one 6 24116125
2023 Expression of the schizophrenia associated gene FEZ1 in the early developing fetal human forebrain. Frontiers in neuroscience 3 37746155
2025 Blood transcriptomics identifies FEZ1 as a potential biomarker for inflammatory bowel disease. Computers in biology and medicine 1 39894009