WDFY3

WDFY3
Identifiers
AliasesWDFY3, ALFY, ZFYVE25, WD repeat and FYVE domain containing 3, BCHS, MCPH18
External IDsOMIM: 617485; MGI: 1096875; GeneCards: WDFY3
Available structures
PDBOrtholog search: PDBe RCSB
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

23001

72145

Ensembl

ENSG00000163625

ENSMUSG00000043940

UniProt

Q8IZQ1

Q6VNB8

RefSeq (mRNA)

NM_014991
NM_178583
NM_178585

NM_172882
NM_028124

RefSeq (protein)

NP_055806

NP_766470

Location (UCSC)Chr 4: 84.67 – 84.97 MbChr 5: 101.98 – 102.22 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse

WD repeat and FYVE domain-containing protein 3 (WDFY3), also known as Autophagy-linked FYVE protein (ALFY), is a large protein encoded by the WDFY3 gene located on human chromosome 4.

Structure

WDFY3 encodes a protein with a N-terminal PH-BEACH domain, 5 WD40 repeats and a C-terminal FYVE domain. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been defined.

Biochemistry and function

Localization

The C-terminal FYVE domain binds phosphatidylinositol-3-phosphate, a nuclear membrane lipid, localizing WDFY3 to the nuclear membrane under normal conditions.

A unique glutamic acid with the FYVE domain reduces membrane binding affinity, allowing WDFY3 to more easily enter the cytosol.

Autophagy

WDFY3 is recruited from the nuclear membrane to cytoplasmic ubiquitin-rich protein aggregates marked by SQSTM1.

It connects these aggregates to macroautophagic proteins such as Atg5, Atg12, Atg16L, and LC3.

LC3 is specifically bound by a LC3-interacting region (LCI) within the WD40 repeat domain of WDFY3.

not necessary for starvation-induced autophagy

Neural development pathways

Establishing neuronal connectivity

directional cell migration

Interaction with neurodegenerative disease pathways

In vitro ALS pathway modification

Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy

PD-like proteome and histology with age

Clinical

Mutations in WDFY3 have been associated with neurodevelopmental delay, intellectual disability, macrocephaly, microcephaly, and neurodevelopmental conditions such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).

Homology

Drosphila: bchs

Research in animal models

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000163625 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000043940 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, et al. (July 1999). "Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 6 (1): 63–70. doi:10.1093/dnares/6.1.63. PMID 10231032.
  6. 1 2 "Entrez Gene: WDFY3 WD repeat and FYVE domain containing 3".
  7. ↑ "Protein structure - WDFY3 - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2026-04-15.
  8. ↑ Simonsen A, Birkeland HC, Gillooly DJ, Mizushima N, Kuma A, Yoshimori T, et al. (August 2004). "Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes". Journal of Cell Science. 117 (Pt 18): 4239–4251. doi:10.1242/jcs.01287. PMID 15292400.
  9. ↑ Reinhart EF, Litt NA, Katzenell S, Pellegrini M, Yamamoto A, Ragusa MJ (January 2021). "A highly conserved glutamic acid in ALFY inhibits membrane binding to aid in aggregate clearance". Traffic. 22 (1–2). Copenhagen, Denmark: 23–37. doi:10.1111/tra.12771. PMC 7902475. PMID 33225481.
  10. ↑ Hocking LJ, Mellis DJ, McCabe PS, Helfrich MH, Rogers MJ (November 2010). "Functional interaction between sequestosome-1/p62 and autophagy-linked FYVE-containing protein WDFY3 in human osteoclasts". Biochemical and Biophysical Research Communications. 402 (3): 543–548. Bibcode:2010BBRC..402..543H. doi:10.1016/j.bbrc.2010.10.076. hdl:2164/2177. PMID 20971078.
  11. ↑ Bjørkøy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, et al. (November 2005). "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death". The Journal of Cell Biology. 171 (4): 603–614. doi:10.1083/jcb.200507002. PMC 2171557. PMID 16286508.
  12. ↑ Clausen TH, Lamark T, Isakson P, Finley K, Larsen KB, Brech A, et al. (April 2010). "p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy". Autophagy. 6 (3): 330–344. doi:10.4161/auto.6.3.11226. PMID 20168092.
  13. 1 2 Le Duc D, Giulivi C, Hiatt SM, Napoli E, Panoutsopoulos A, Harlan De Crescenzo A, Kotzaeridou U, Syrbe S, Anagnostou E, Azage M, Bend R, Begtrup A, Brown NJ, Büttner B, Cho MT, Cooper GM, Doering JH, Dubourg C, Everman DB10, Hildebrand MS12,17, Santos FJR, Kellam B, Keller-Ramey J, Lemke JR, Liu S11, Niyazov D, Payne K, Person R, Quélin C, Schnur RE, Smith BT, Strober J, Walker S, Wallis M, Walsh L, Yang S, Yuen RKC, Ziegler A, Sticht H, Pride MC, Orosco L, Martínez-Cerdeño V, Silverman JL, Crawley JN, Scherer SW, Zarbalis KS, Jamra R (2019) Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size. Brain
  14. ↑ Yamamoto A, Simonsen A (2011). "Alfy-dependent elimination of aggregated proteins by macroautophagy". Autophagy. 7 (3): 346–350. doi:10.4161/auto.7.3.14234. PMC 3060415. PMID 21150266.
  15. 1 2 Lystad AH, Ichimura Y, Takagi K, Yang Y, Pankiv S, Kanegae Y, et al. (May 2014). "Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures". EMBO Reports. 15 (5): 557–565. doi:10.1002/embr.201338003. PMC 4210083. PMID 24668264.
  16. ↑ Shi J, Wu X, Wang Z, Li F, Meng Y, Moore RM, et al. (December 2022). "A genome-wide CRISPR screen identifies WDFY3 as a regulator of macrophage efferocytosis". Nature Communications. 13 (1) 7929. Bibcode:2022NatCo..13.7929S. doi:10.1038/s41467-022-35604-8. PMC 9789999. PMID 36566259.
  17. ↑ Dragich JM, Kuwajima T, Hirose-Ikeda M, Yoon MS, Eenjes E, Bosco JR, et al. (September 2016). "Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain". eLife. 5 e14810. doi:10.7554/eLife.14810. PMC 5030082. PMID 27648578.
  18. ↑ Søreng K, Pankiv S, Bergsmark C, Haugsten EM, Dahl AK, de la Ballina LR, et al. (February 2022). "ALFY localizes to early endosomes and cellular protrusions to facilitate directional cell migration". Journal of Cell Science. 135 (4) jcs259138. doi:10.1242/jcs.259138. PMC 8919339. PMID 35099014.
  19. ↑ Han H, Wei W, Duan W, Guo Y, Li Y, Wang J, et al. (March 2015). "Autophagy-linked FYVE protein (Alfy) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)". In Vitro Cellular & Developmental Biology. Animal. 51 (3): 249–263. doi:10.1007/s11626-014-9832-4. PMID 25385288.
  20. ↑ Fox LM, Kim K, Johnson CW, Chen S, Croce KR, Victor MB, et al. (March 2020). "Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy". Neuron. 105 (5): 813–821.e6. doi:10.1016/j.neuron.2019.12.003. PMC 7060123. PMID 31899071.
  21. ↑ Vorkapich A, Mustafa A, Flores-Torres AL, Zarbalis KS, Giulivi C (April 2026). "Wdfy3-dependent autophagy impairment recapitulates presymptomatic neurodegenerative signatures in mice". Scientific Reports. 16 (1) 16229. doi:10.1038/s41598-026-43314-0. PMC 13201858. PMID 41935068.
  22. ↑ Kadir R, Harel T, Markus B, Perez Y, Bakhrat A, Cohen I, et al. (March 2016). "ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size". PLoS Genetics. 12 (3) e1005919. doi:10.1371/journal.pgen.1005919. PMC 4805177. PMID 27008544.
  23. ↑ Finley KD, Edeen PT, Cumming RC, Mardahl-Dumesnil MD, Taylor BJ, Rodriguez MH, et al. (February 2003). "blue cheese mutations define a novel, conserved gene involved in progressive neural degeneration". The Journal of Neuroscience. 23 (4): 1254–1264. doi:10.1523/JNEUROSCI.23-04-01254.2003. PMC 1975817. PMID 12598614.

Further reading