A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium
Mutations in tripeptidyl peptidase 1 (TPP1) have been associated with late infantile neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disorder. TPP1 is a lysosomal serine protease, which removes tripeptides from the N-terminus of proteins and is composed of an N-terminal prodomain and a cat...
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The Company of Biologists
2017-07-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/10/7/897 |
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| author | Maria Stumpf Rolf Müller Berthold Gaßen Regina Wehrstedt Petra Fey Malte A. Karow Ludwig Eichinger Gernot Glöckner Angelika A. Noegel |
| author_facet | Maria Stumpf Rolf Müller Berthold Gaßen Regina Wehrstedt Petra Fey Malte A. Karow Ludwig Eichinger Gernot Glöckner Angelika A. Noegel |
| author_sort | Maria Stumpf |
| collection | DOAJ |
| description | Mutations in tripeptidyl peptidase 1 (TPP1) have been associated with late infantile neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disorder. TPP1 is a lysosomal serine protease, which removes tripeptides from the N-terminus of proteins and is composed of an N-terminal prodomain and a catalytic domain. It is conserved in mammals, amphibians, fish and the amoeba Dictyostelium discoideum. D. discoideum harbors at least six genes encoding TPP1, tpp1A to tpp1F. We identified TPP1F as binding partner of Dictyostelium GPHR (Golgi pH regulator), which is an evolutionarily highly conserved intracellular transmembrane protein. A region encompassing the DUF3735 (GPHR_N) domain of GPHR was responsible for the interaction. In TPP1F, the binding site is located in the prodomain of the protein. The tpp1F gene is transcribed throughout development and translated into a polypeptide of ∼65 kDa. TPP1 activity was demonstrated for TPP1F-GFP immunoprecipitated from D. discoideum cells. Its activity could be inhibited by addition of the recombinant DUF3735 domain of GPHR. Knockout tpp1F mutants did not display any particular phenotype, and TPP1 activity was not abrogated, presumably because tpp1B compensates as it has the highest expression level of all the TPP1 genes during growth. The GPHR interaction was not restricted to TPP1F but occurred also with TPP1B. As previous reports show that the majority of the TPP1 mutations in NCL resulted in reduction or loss of enzyme activity, we suggest that Dicyostelium could be used as a model system in which to test new reagents that could affect the activity of the protein and ameliorate the disease. |
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| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-14T13:27:02Z |
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| publisher | The Company of Biologists |
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| series | Disease Models & Mechanisms |
| spelling | doaj.art-a6e224ba147a4d4faf20a060ea74f3c82022-12-21T22:59:48ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112017-07-0110789790710.1242/dmm.029280029280A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in DictyosteliumMaria Stumpf0Rolf Müller1Berthold Gaßen2Regina Wehrstedt3Petra Fey4Malte A. Karow5Ludwig Eichinger6Gernot Glöckner7Angelika A. Noegel8 Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Dicty Base, Northwestern University, Biomedical Informatics Center and Center for Genetic Medicine, Chicago, IL 60611, USA Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Institute of Biochemistry I, Medical Faculty, University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-Str. 52, Köln 50931, Germany Mutations in tripeptidyl peptidase 1 (TPP1) have been associated with late infantile neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disorder. TPP1 is a lysosomal serine protease, which removes tripeptides from the N-terminus of proteins and is composed of an N-terminal prodomain and a catalytic domain. It is conserved in mammals, amphibians, fish and the amoeba Dictyostelium discoideum. D. discoideum harbors at least six genes encoding TPP1, tpp1A to tpp1F. We identified TPP1F as binding partner of Dictyostelium GPHR (Golgi pH regulator), which is an evolutionarily highly conserved intracellular transmembrane protein. A region encompassing the DUF3735 (GPHR_N) domain of GPHR was responsible for the interaction. In TPP1F, the binding site is located in the prodomain of the protein. The tpp1F gene is transcribed throughout development and translated into a polypeptide of ∼65 kDa. TPP1 activity was demonstrated for TPP1F-GFP immunoprecipitated from D. discoideum cells. Its activity could be inhibited by addition of the recombinant DUF3735 domain of GPHR. Knockout tpp1F mutants did not display any particular phenotype, and TPP1 activity was not abrogated, presumably because tpp1B compensates as it has the highest expression level of all the TPP1 genes during growth. The GPHR interaction was not restricted to TPP1F but occurred also with TPP1B. As previous reports show that the majority of the TPP1 mutations in NCL resulted in reduction or loss of enzyme activity, we suggest that Dicyostelium could be used as a model system in which to test new reagents that could affect the activity of the protein and ameliorate the disease.http://dmm.biologists.org/content/10/7/897Neuronal ceroid lipofuscinosis (NCL)Tripeptidyl peptidase 1 (TPP1)Golgi pH regulator (GPHR)EndosomesLysosomes |
| spellingShingle | Maria Stumpf Rolf Müller Berthold Gaßen Regina Wehrstedt Petra Fey Malte A. Karow Ludwig Eichinger Gernot Glöckner Angelika A. Noegel A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium Disease Models & Mechanisms Neuronal ceroid lipofuscinosis (NCL) Tripeptidyl peptidase 1 (TPP1) Golgi pH regulator (GPHR) Endosomes Lysosomes |
| title | A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium |
| title_full | A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium |
| title_fullStr | A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium |
| title_full_unstemmed | A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium |
| title_short | A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium |
| title_sort | tripeptidyl peptidase 1 is a binding partner of the golgi ph regulator gphr in dictyostelium |
| topic | Neuronal ceroid lipofuscinosis (NCL) Tripeptidyl peptidase 1 (TPP1) Golgi pH regulator (GPHR) Endosomes Lysosomes |
| url | http://dmm.biologists.org/content/10/7/897 |
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