HGNC Approved Gene Symbol: ANKRD50
Cytogenetic location: 4q28.1 Genomic coordinates (GRCh38): 4:124,664,048-124,712,732 (from NCBI)
ANKRD50 is an essential component of the SNX27 (611541)-retromer (see VPS35, 601501)-WASH (see WASHC1, 613632) super complex that is involved in endosome-to-plasma membrane trafficking (Kvainickas et al., 2017).
Kvainickas et al. (2017) determined that the 1,429-amino acid human ANKRD50 protein contains a highly folded globular N-terminal domain, followed by 19 ankyrin repeats that form a large U-shaped domain, and 2 extended C-terminal helical domains. The C terminus of ANKRD50 also harbors a PDZ domain-binding motif. Immunofluorescence analysis revealed that ANKRD50 with an N-terminal GFP tag localized specifically to retromer- and recycling cargo-enriched endosomes in a perinuclear area near the trans-Golgi network in human RPE1 cells. The localization required the C-terminal domains of ANKRD50.
Gross (2022) mapped the ANKRD50 gene to chromosome 4q28.1 based on an alignment of the ANKRD50 sequence (GenBank BC024725) with the genomic sequence (GRCh38).
Using quantitative proteomic analysis, McGough et al. (2014) showed that human ANKRD50 interacted with human VPS35, a core retromer component. Knockdown of ANKRD50 in HeLa cells affected retromer-mediated endosome-to-plasma-membrane trafficking, phenocopying loss of SNX27-retromer function. In addition, ANKRD50 knockdown resulted in decreased cell-surface expression of CD97 (ADGRE5; 601211) and TRAILR1 (TNFRSF10A; 603611), leading to increased intracellular accumulation of these proteins.
Using knockdown analysis in human U2OS cells, Kvainickas et al. (2017) showed that ANKRD50 interacted with the multiple components of the SNX27-retromer-WASH super complex and was required for SNX27-retromer-WASH complex-mediated endosome-to-plasma membrane trafficking of PDZ ligand-bearing transmembrane proteins and several integrins. Specifically, ANKRD50 interacted directly with SNX27 through the C-terminal PDZ-binding motif ANKRD50, with VPS35 in the retromer trimer through a motif spanning residues tyr1299 to phe1304 of ANKRD50, and with FAM21 (WASH2C2; 613631) of the WASH complex through the N-terminal domain of ANKRD50. Knockdown and reexpression experiments in HeLa cells revealed that all ANKRD50 interactions were required for efficient recycling of SNX27-retromer-WASH-dependent cargo.
Gross, M. B. Personal Communication. Baltimore, Md. 4/25/2022.
Kvainickas, A., Jimenez Orgaz, A., Nagele, H., Diedrich, B., Heesom, K. J., Dengjel, J., Cullen, P. J., Steinberg, F. Retromer- and WASH-dependent sorting of nutrient transporters requires a multivalent interaction network with ANKRD50. J. Cell Sci. 130: 382-395, 2017. [PubMed: 27909246] [Full Text: https://doi.org/10.1242/jcs.196758]
McGough, I. J., Steinberg, F., Gallon, M., Yatsu, A., Ohbayashi, N., Heesom, K. J., Fukuda, M., Cullen, P. J. Identification of molecular heterogeneity in SNK27-retromer-mediated endosome-to-plasma-membrane recycling. J. Cell Sci. 127: 4940-4953, 2014. [PubMed: 25278552] [Full Text: https://doi.org/10.1242/jcs.156299]