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PMID:22693585

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Citation

Collin, GB, Marshall, JD, King, BL, Milan, G, Maffei, P, Jagger, DJ and Naggert, JK (2012) The Alström syndrome protein, ALMS1, interacts with α-actinin and components of the endosome recycling pathway. PLoS ONE 7:e37925

Abstract

Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS.

Links

PubMed PMC3365098 Online version:10.1371/journal.pone.0037925

Keywords

Actinin/chemistry; Actinin/metabolism; Alstrom Syndrome/metabolism; Alstrom Syndrome/pathology; Amino Acid Sequence; Animals; Cell Line; Cilia/metabolism; Cytokinesis; Dogs; Endocytosis; Endosomes/metabolism; Fibroblasts/pathology; Humans; Mice; Molecular Sequence Data; Protein Binding; Protein Isoforms/chemistry; Protein Isoforms/metabolism; Protein Structure, Tertiary; Protein Transport; Proteins/chemistry; Proteins/metabolism; Stress Fibers/metabolism; Stress Fibers/pathology; Transferrin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ACTN3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8K4E0

F

Seeded From UniProt

complete

MOUSE:ACTN4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8K4E0

F

Seeded From UniProt

complete

MOUSE:ACTN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8K4E0

F

Seeded From UniProt

complete

MOUSE:ALMS1

enables

GO:0051393: alpha-actinin binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O88990
PR:P57780
PR:Q7TPR4
PR:Q9JI91

F

Seeded From UniProt

complete

HUMAN:ALMS1

acts_upstream_of_or_within

GO:0016197: endosomal transport

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ALMS1

acts_upstream_of_or_within

GO:0051492: regulation of stress fiber assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ACTN2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8K4E0

F

Seeded From UniProt

complete


See also

References

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