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PMID:20168298

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Citation

Giamarchi, A, Feng, S, Rodat-Despoix, L, Xu, Y, Bubenshchikova, E, Newby, LJ, Hao, J, Gaudioso, C, Crest, M, Lupas, AN, Honoré, E, Williamson, MP, Obara, T, Ong, AC and Delmas, P (2010) A polycystin-2 (TRPP2) dimerization domain essential for the function of heteromeric polycystin complexes. EMBO J. 29:1176-91

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Earlier work has shown that PC1 and PC2 assemble into a polycystin complex implicated in kidney morphogenesis. PC2 also assembles into homomers of uncertain functional significance. However, little is known about the molecular mechanisms that direct polycystin complex assembly and specify its functions. We have identified a coiled coil in the C-terminus of PC2 that functions as a homodimerization domain essential for PC1 binding but not for its self-oligomerization. Dimerization-defective PC2 mutants were unable to reconstitute PC1/PC2 complexes either at the plasma membrane (PM) or at PM-endoplasmic reticulum (ER) junctions but could still function as ER Ca(2+)-release channels. Expression of dimerization-defective PC2 mutants in zebrafish resulted in a cystic phenotype but had lesser effects on organ laterality. We conclude that C-terminal dimerization of PC2 specifies the formation of polycystin complexes but not formation of ER-localized PC2 channels. Mutations that affect PC2 C-terminal homo- and heteromerization are the likely molecular basis of cyst formation in ADPKD.

Links

PubMed PMC2857461 Online version:10.1038/emboj.2010.18

Keywords

Amino Acid Sequence; Animals; Calcium/metabolism; Cell Line; Dimerization; Endoplasmic Reticulum/metabolism; Endoplasmic Reticulum/ultrastructure; Gene Expression; Humans; Kidney/pathology; Molecular Sequence Data; Mutation; Polycystic Kidney, Autosomal Dominant/genetics; Protein Binding; Protein Structure, Tertiary; Sequence Alignment; TRPP Cation Channels/chemistry; TRPP Cation Channels/genetics; TRPP Cation Channels/metabolism; Two-Hybrid System Techniques; Zebrafish/genetics

Significance

Annotations

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

HUMAN:PKD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13563

F

Seeded From UniProt

complete

HUMAN:PKD2

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13563

F

Seeded From UniProt

complete

HUMAN:PKD2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P98161

F

Seeded From UniProt

complete

DANRE:PKD2

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060630-4

P

Seeded From UniProt

complete

DANRE:PKD2

involved_in

GO:0072114: pronephros morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060630-4

P

Seeded From UniProt

complete

DANRE:Q6IVV8

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060630-4

P

Seeded From UniProt

complete

DANRE:Q6IVV8

involved_in

GO:0072114: pronephros morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060630-4

P

Seeded From UniProt

complete

DANRE:Q2VF27

involved_in

GO:0072114: pronephros morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060630-4

P

Seeded From UniProt

complete

DANRE:Q2VF27

involved_in

GO:0007368: determination of left/right symmetry

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-060630-4

P

Seeded From UniProt

complete


See also

References

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