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

Further reading