WDFY3

WDFY3
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	3WIM
Identifiers
Aliases	WDFY3, ALFY, ZFYVE25, WD repeat and FYVE domain containing 3, BCHS, MCPH18
External IDs	OMIM: 617485; MGI: 1096875; HomoloGene: 22855; GeneCards: WDFY3; OMA:WDFY3 - orthologs
Gene location (Human)
Chr.	Chromosome 4 (human)
End	84,966,690 bp
Gene location (Mouse)
Chr.	Chromosome 5 (mouse)
End	102,217,787 bp
RNA expression pattern
	Top expressed in
	sural nerve; ; Achilles tendon; ; corpus callosum; ; inferior olivary nucleus; ; dorsal motor nucleus of vagus nerve; ; ventricular zone; ; internal globus pallidus; ; ganglionic eminence; ; epithelium of colon; ; optic nerve;
	Top expressed in
	mammillary body; ; lateral hypothalamus; ; lateral septal nucleus; ; lobe of cerebellum; ; lateral geniculate nucleus; ; cerebellar vermis; ; dorsal tegmental nucleus; ; ventromedial nucleus; ; paraventricular nucleus of hypothalamus; ; medial dorsal nucleus;
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	protein binding; 1-phosphatidylinositol binding; beta-N-acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase activity; metal ion binding; lipid binding;
Cellular component	Atg12-Atg5-Atg16 complex; PML body; nuclear membrane; nuclear envelope; extrinsic component of membrane; extrinsic component of autophagosome membrane; autophagosome; cytoplasm; inclusion body; membrane; nucleus; nucleolus; plasma membrane; cytosol; axon; cell projection; perikaryon;
Biological process	aggrephagy; autophagy; multicellular organism development;
	Sources:Amigo / QuickGO
Orthologs
	23001
	72145
	ENSG00000163625
	ENSMUSG00000043940
	Q8IZQ1
	Q6VNB8
	NM_014991; NM_178583; NM_178585
	NM_172882; NM_028124
	NP_055806
	NP_766470
	Wikidata
View/Edit Human	View/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 4.⁵⁶⁷

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.⁶

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 conditions⁸.

A unique glutamic acid with the FYVE domain reduces membrane binding affinity, allowing WDFY3 to more easily enter the cytosol.⁹

Autophagy

WDFY3 is recruited from the nuclear membrane to cytoplasmic ubiquitin-rich protein aggregates marked by SQSTM1.¹⁰¹¹¹².

It connects these aggregates to macroautophagic proteins such as Atg5, Atg12, Atg16L, and LC3.¹³¹⁴¹⁵

LC3 is specifically bound by a LC3-interacting region (LCI) within the WD40 repeat domain of WDFY3.¹⁵¹⁶

not necessary for starvation-induced autophagy

Neural development pathways

Establishing neuronal connectivity¹⁷

directional cell migration¹⁸

Interaction with neurodegenerative disease pathways

In vitro ALS pathway modification¹⁹

Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy²⁰

PD-like proteome and histology with age²¹

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).¹³²²

Homology

Drosphila: bchs²³

Research in Animal Models

References

GRCh38: Ensembl release 89: ENSG00000163625 – Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000043940 – Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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"Entrez Gene: WDFY3 WD repeat and FYVE domain containing 3".
"Protein structure - WDFY3 - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2026-04-15.
Simonsen, Anne; Birkeland, Hanne C. G.; Gillooly, David J.; Mizushima, Noboru; Kuma, Akiko; Yoshimori, Tamotsu; Slagsvold, Thomas; Brech, Andreas; Stenmark, Harald (2004-08-15). "Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes". Journal of Cell Science. 117 (18): 4239–4251. doi:10.1242/jcs.01287. ISSN 1477-9137. PMID 15292400.
Reinhart, Erin F.; Litt, Nicole A.; Katzenell, Sarah; Pellegrini, Maria; Yamamoto, Ai; Ragusa, Michael J. (January 2021). "A highly conserved glutamic acid in ALFY inhibits membrane binding to aid in aggregate clearance". Traffic (Copenhagen, Denmark). 22 (1–2): 23–37. doi:10.1111/tra.12771. ISSN 1600-0854. PMC 7902475. PMID 33225481.
Hocking, Lynne J.; Mellis, David J.; McCabe, Paul S.; Helfrich, Miep H.; Rogers, Michael J. (2010-11-19). "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. ISSN 0006-291X. PMID 20971078.
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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
Yamamoto, Ai; Simonsen, Anne (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.
Lystad, Alf Håkon; Ichimura, Yoshinobu; Takagi, Kenji; Yang, Yinjie; Pankiv, Serhiy; Kanegae, Yumi; Kageyama, Shun; Suzuki, Mariko; Saito, Izumu; Mizushima, Tsunehiro; Komatsu, Masaaki; Simonsen, Anne (2014-05-01). "Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures". The EMBO Reports. 15 (5): 557–565. doi:10.1002/embr.201338003. ISSN 1469-3178. PMC 4210083. PMID 24668264.
Shi, Jianting; Wu, Xun; Wang, Ziyi; Li, Fang; Meng, Yujiao; Moore, Rebecca M.; Cui, Jian; Xue, Chenyi; Croce, Katherine R.; Yurdagul, Arif; Doench, John G.; Li, Wei; Zarbalis, Konstantinos S.; Tabas, Ira; Yamamoto, Ai (2022-12-24). "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. ISSN 2041-1723. PMC 9789999. PMID 36566259.
Dragich, Joanna M.; Kuwajima, Takaaki; Hirose-Ikeda, Megumi; Yoon, Michael S.; Eenjes, Evelien; Bosco, Joan R.; Fox, Leora M.; Lystad, Alf H.; Oo, Tinmarla F.; Yarygina, Olga; Mita, Tomohiro; Waguri, Satoshi; Ichimura, Yoshinobu; Komatsu, Masaaki; Simonsen, Anne (2016-09-20). "Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain". eLife. 5 e14810. doi:10.7554/eLife.14810. ISSN 2050-084X. PMC 5030082. PMID 27648578.
Søreng, Kristiane; Pankiv, Serhiy; Bergsmark, Camilla; Haugsten, Ellen M.; Dahl, Anette K.; de la Ballina, Laura R.; Yamamoto, Ai; Lystad, Alf H.; Simonsen, Anne (2022-02-15). "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. ISSN 1477-9137. PMC 8919339. PMID 35099014.
Han, Huihui; Wei, Wanyi; Duan, Weisong; Guo, Yansu; Li, Yi; Wang, Jie; Bi, Yue; Li, Chunyan (2015-03-01). "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. ISSN 1543-706X. PMID 25385288.
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