ANKRD50

UniProt ID: Q9ULJ7
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

ANKRD50 (ankyrin repeat domain-containing 50) is a component of the endosomal SNX27-retromer-WASH sorting machinery. Found as a VPS35-interacting protein, it binds several parts of the SNX27-retromer-WASH complex directly and cooperatively, and is needed to recycle transmembrane cargo such as GLUT1 and the amino acid transporter SLC1A4 from endosomes to the plasma membrane; without it these cargoes are routed to lysosomes. The Parkinson's disease mutation D620N in VPS35 weakens retromer's association with ANKRD50, and ANKRD50 has itself been proposed as a candidate Parkinson's disease gene.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005515 protein binding
IPI
PMID:21911577
A physical interaction network of dengue virus and human pro... 		REMOVE
Summary: Protein binding (IPI) with a dengue virus protein from a virus-host interaction screen. There is no follow-up for ANKRD50, and GO:0005515 is uninformative.
Reason: The interaction is deposited as [file:human/ANKRD50/ANKRD50-uniprot.txt "CC Q9ULJ7; PRO_0000308465 [P29991]; Xeno; NbExp=4; IntAct=EBI-5653671, EBI-8826747;"], from a proteome-scale dengue-human interaction map; it says nothing about ANKRD50's cellular function.
Supporting Evidence:
file:human/ANKRD50/ANKRD50-uniprot.txt
CC Q9ULJ7; PRO_0000308465 [P29991]; Xeno; NbExp=4; IntAct=EBI-5653671, EBI-8826747;
GO:0005515 protein binding
IPI
PMID:25278552
Identification of molecular heterogeneity in SNX27-retromer-... 		MODIFY
Summary: Protein binding (IPI) with VPS35, the core retromer subunit. ANKRD50 was identified in the VPS35 interactome and binds several parts of the SNX27-retromer-WASH machinery directly; modified to retromer complex binding.
Reason: [PMID:25278552 "This has identified a number of new interacting proteins, including ankyrin-repeat domain 50 (ANKRD50), seriologically defined colon cancer antigen 3 (SDCCAG3) and VPS9-ankyrin-repeat protein (VARP, also known as ANKRD27)."] [PMID:27909246 "Mechanistically, we show that ANKRD50 simultaneously engages multiple parts of the SNX27-retromer-WASH complex machinery in a direct and co-operative interaction network"]
Proposed replacements: retromer complex binding
Supporting Evidence:
PMID:25278552
This has identified a number of new interacting proteins, including ankyrin-repeat domain 50 (ANKRD50), seriologically defined colon cancer antigen 3 (SDCCAG3) and VPS9-ankyrin-repeat protein (VARP, also known as ANKRD27).
PMID:27909246
Mechanistically, we show that ANKRD50 simultaneously engages multiple parts of the SNX27-retromer-WASH complex machinery in a direct and co-operative interaction network
GO:0005768 endosome
IEA
GO_REF:0000044 		ACCEPT
Summary: Endosome (IEA, UniProt subcellular location by curator inference). Consistent with ANKRD50 acting in the endosomal SNX27-retromer-WASH complex; accepted.
Reason: UniProt records [file:human/ANKRD50/ANKRD50-uniprot.txt "CC -!- SUBCELLULAR LOCATION: Endosome {ECO:0000305}."] (ECO:0000305). [PMID:27909246 "Here, we firmly establish ANKRD50 as a new and essential component of the SNX27-retromer-WASH super complex."]
Supporting Evidence:
file:human/ANKRD50/ANKRD50-uniprot.txt
CC -!- SUBCELLULAR LOCATION: Endosome {ECO:0000305}.
PMID:27909246
Here, we firmly establish ANKRD50 as a new and essential component of the SNX27-retromer-WASH super complex.
GO:0032456 endocytic recycling
IMP
PMID:25278552
Identification of molecular heterogeneity in SNX27-retromer-... 		ACCEPT
Summary: Endocytic recycling (IMP). Depleting ANKRD50 phenocopies loss of SNX27-retromer, sending recycling cargo such as GLUT1 to lysosomes instead of the cell surface; ANKRD50 is a component of the machinery, so this is participation; accepted as core.
Reason: [PMID:25278552 "Like suppression of VPS35, suppression of ANKRD50 resulted in a loss of GLUT1 expression at the cell surface"] [PMID:25278552 "Taken together, these data identify a role for ANKRD50 in the endosome-to-plasma-membrane sorting of multiple cargos and provide evidence that, mechanistically, its role in this process is linked with the SNX27–retromer sorting complex."] [PMID:27909246 "Here, we firmly establish ANKRD50 as a new and essential component of the SNX27-retromer-WASH super complex."]
Supporting Evidence:
PMID:25278552
Like suppression of VPS35, suppression of ANKRD50 resulted in a loss of GLUT1 expression at the cell surface
PMID:25278552
Taken together, these data identify a role for ANKRD50 in the endosome-to-plasma-membrane sorting of multiple cargos and provide evidence that, mechanistically, its role in this process is linked with the SNX27–retromer sorting complex.
PMID:27909246
Here, we firmly establish ANKRD50 as a new and essential component of the SNX27-retromer-WASH super complex.

Core Functions

Component of the endosomal SNX27-retromer-WASH sorting machinery that binds retromer and associated factors to recycle transmembrane cargo, such as GLUT1 and SLC1A4, from endosomes to the plasma membrane.

Molecular Function:
retromer complex binding
Directly Involved In:
endocytic recycling
Cellular Locations:
endosome
Supporting Evidence:
  • PMID:25278552
    This has identified a number of new interacting proteins, including ankyrin-repeat domain 50 (ANKRD50), seriologically defined colon cancer antigen 3 (SDCCAG3) and VPS9-ankyrin-repeat protein (VARP, also known as ANKRD27).
  • PMID:27909246
    Here, we firmly establish ANKRD50 as a new and essential component of the SNX27-retromer-WASH super complex.
  • PMID:27909246
    Mechanistically, we show that ANKRD50 simultaneously engages multiple parts of the SNX27-retromer-WASH complex machinery in a direct and co-operative interaction network
  • PMID:25278552
    Like suppression of VPS35, suppression of ANKRD50 resulted in a loss of GLUT1 expression at the cell surface

References

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Suggested Questions for Experts

Q: Which surfaces of ANKRD50 contact SNX27, retromer and WASH, and does its ankyrin domain bridge them?

Q: Does the VPS35 D620N Parkinson's mutation impair cargo recycling through loss of ANKRD50 association?

Suggested Experiments

Experiment: Map the ANKRD50 binding sites on SNX27, VPS35 and the WASH complex with purified proteins, and test which are needed to rescue GLUT1 recycling in ANKRD50-depleted cells.

Deep Research

Affinage

(ANKRD50-deep-research-affinage.md)

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📚 Additional Documentation

Notes

(ANKRD50-notes.md)

ANKRD50 notes

  • ANKRD50 was found in the VPS35 interactome, and its RNAi depletion phenocopies loss of SNX27-retromer: GLUT1 is lost from the surface and routed to lysosomes [PMID:25278552, full text]. It is an essential component of the SNX27-retromer-WASH supercomplex and binds several parts of it directly and cooperatively. The cargoes include SLC1A4, and VPS35 D620N weakens retromer's association with ANKRD50 [PMID:27909246, abstract].
  • Endocytic recycling (IMP): ACCEPT, core. ANKRD50 is a component of the machinery, so this is participation. Endosome (IEA): ACCEPT.
  • VPS35 IPI → MODIFY to GO:1905394 retromer complex binding. Dengue-virus IPI → REMOVE.
  • Candidate late-onset PD gene in a family exome study PMID:40494419; no GO term drawn.
  • PTHR24173 (shared with ANKRD16 and ANKRD28) is a large mixed family whose annotated nodes do not reach ANKRD50 (PAN-GO 0). The family files are not committed, consistent with the ANKRD16 and ANKRD28 reviews.

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