Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals.
Mutations in PKD1, the gene encoding for the receptor Polycystin-1 (PC-1), cause autosomal dominant polycystic kidney disease (ADPKD). The cytoplasmic C-terminus of PC-1 contains a coiled-coil domain that mediates an interaction with the PKD2 gene product, Polycystin-2 (PC-2). Here we identify a nov...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-09-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2939065?pdf=render |
| _version_ | 1828762321783095296 |
|---|---|
| author | Claas Wodarczyk Gianfranco Distefano Isaline Rowe Massimiliano Gaetani Barbara Bricoli Mordi Muorah Andrea Spitaleri Valeria Mannella Piero Ricchiuto Monika Pema Maddalena Castelli Ariel E Casanova Luca Mollica Manuela Banzi Manila Boca Corinne Antignac Sophie Saunier Giovanna Musco Alessandra Boletta |
| author_facet | Claas Wodarczyk Gianfranco Distefano Isaline Rowe Massimiliano Gaetani Barbara Bricoli Mordi Muorah Andrea Spitaleri Valeria Mannella Piero Ricchiuto Monika Pema Maddalena Castelli Ariel E Casanova Luca Mollica Manuela Banzi Manila Boca Corinne Antignac Sophie Saunier Giovanna Musco Alessandra Boletta |
| author_sort | Claas Wodarczyk |
| collection | DOAJ |
| description | Mutations in PKD1, the gene encoding for the receptor Polycystin-1 (PC-1), cause autosomal dominant polycystic kidney disease (ADPKD). The cytoplasmic C-terminus of PC-1 contains a coiled-coil domain that mediates an interaction with the PKD2 gene product, Polycystin-2 (PC-2). Here we identify a novel domain in the PC-1 C-terminal tail, a polyproline motif mediating an interaction with Src homology domain 3 (SH3). A screen for interactions using the PC-1 C-terminal tail identified the SH3 domain of nephrocystin-1 (NPHP1) as a potential binding partner of PC-1. NPHP1 is the product of a gene that is mutated in a different form of renal cystic disease, nephronophthisis (NPHP). We show that in vitro pull-down assays and NMR structural studies confirmed the interaction between the PC-1 polyproline motif and the NPHP1 SH3 domain. Furthermore, the two full-length proteins interact through these domains; using a recently generated model system allowing us to track endogenous PC-1, we confirm the interaction between the endogenous proteins. Finally, we show that NPHP1 trafficking to cilia does not require PC-1 and that PC-1 may require NPHP1 to regulate resistance to apoptosis, but not to regulate cell cycle progression. In line with this, we find high levels of apoptosis in renal specimens of NPHP patients. Our data uncover a link between two different ciliopathies, ADPKD and NPHP, supporting the notion that common pathogenetic defects, possibly involving de-regulated apoptosis, underlie renal cyst formation. |
| first_indexed | 2024-12-11T01:42:48Z |
| format | Article |
| id | doaj.art-d97fd883beff4166a381e507fa9f5edf |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T01:42:48Z |
| publishDate | 2010-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-d97fd883beff4166a381e507fa9f5edf2022-12-22T01:24:59ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-09-0159e1271910.1371/journal.pone.0012719Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals.Claas WodarczykGianfranco DistefanoIsaline RoweMassimiliano GaetaniBarbara BricoliMordi MuorahAndrea SpitaleriValeria MannellaPiero RicchiutoMonika PemaMaddalena CastelliAriel E CasanovaLuca MollicaManuela BanziManila BocaCorinne AntignacSophie SaunierGiovanna MuscoAlessandra BolettaMutations in PKD1, the gene encoding for the receptor Polycystin-1 (PC-1), cause autosomal dominant polycystic kidney disease (ADPKD). The cytoplasmic C-terminus of PC-1 contains a coiled-coil domain that mediates an interaction with the PKD2 gene product, Polycystin-2 (PC-2). Here we identify a novel domain in the PC-1 C-terminal tail, a polyproline motif mediating an interaction with Src homology domain 3 (SH3). A screen for interactions using the PC-1 C-terminal tail identified the SH3 domain of nephrocystin-1 (NPHP1) as a potential binding partner of PC-1. NPHP1 is the product of a gene that is mutated in a different form of renal cystic disease, nephronophthisis (NPHP). We show that in vitro pull-down assays and NMR structural studies confirmed the interaction between the PC-1 polyproline motif and the NPHP1 SH3 domain. Furthermore, the two full-length proteins interact through these domains; using a recently generated model system allowing us to track endogenous PC-1, we confirm the interaction between the endogenous proteins. Finally, we show that NPHP1 trafficking to cilia does not require PC-1 and that PC-1 may require NPHP1 to regulate resistance to apoptosis, but not to regulate cell cycle progression. In line with this, we find high levels of apoptosis in renal specimens of NPHP patients. Our data uncover a link between two different ciliopathies, ADPKD and NPHP, supporting the notion that common pathogenetic defects, possibly involving de-regulated apoptosis, underlie renal cyst formation.http://europepmc.org/articles/PMC2939065?pdf=render |
| spellingShingle | Claas Wodarczyk Gianfranco Distefano Isaline Rowe Massimiliano Gaetani Barbara Bricoli Mordi Muorah Andrea Spitaleri Valeria Mannella Piero Ricchiuto Monika Pema Maddalena Castelli Ariel E Casanova Luca Mollica Manuela Banzi Manila Boca Corinne Antignac Sophie Saunier Giovanna Musco Alessandra Boletta Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. PLoS ONE |
| title | Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. |
| title_full | Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. |
| title_fullStr | Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. |
| title_full_unstemmed | Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. |
| title_short | Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. |
| title_sort | nephrocystin 1 forms a complex with polycystin 1 via a polyproline motif sh3 domain interaction and regulates the apoptotic response in mammals |
| url | http://europepmc.org/articles/PMC2939065?pdf=render |
| work_keys_str_mv | AT claaswodarczyk nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT gianfrancodistefano nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT isalinerowe nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT massimilianogaetani nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT barbarabricoli nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT mordimuorah nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT andreaspitaleri nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT valeriamannella nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT pieroricchiuto nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT monikapema nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT maddalenacastelli nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT arielecasanova nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT lucamollica nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT manuelabanzi nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT manilaboca nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT corinneantignac nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT sophiesaunier nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT giovannamusco nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals AT alessandraboletta nephrocystin1formsacomplexwithpolycystin1viaapolyprolinemotifsh3domaininteractionandregulatestheapoptoticresponseinmammals |