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.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
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
Further reading