Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention
Abstract Positively charged residues are commonly located near the cytoplasm-membrane interface, which is known as the positive-inside rule in membrane topology. The mechanism underlying the function of these charged residues remains poorly understood. Herein, we studied the function of cytoplasmic...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07545-7 |
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| author | Hui Li Shijin Sun Wenjun Guo Lina Wang Zihao Zhang Yue Zhang Ce Zhang Meng Liu Shengnan Zhang Yayan Niu Ningzheng Dong Qingyu Wu |
| author_facet | Hui Li Shijin Sun Wenjun Guo Lina Wang Zihao Zhang Yue Zhang Ce Zhang Meng Liu Shengnan Zhang Yayan Niu Ningzheng Dong Qingyu Wu |
| author_sort | Hui Li |
| collection | DOAJ |
| description | Abstract Positively charged residues are commonly located near the cytoplasm-membrane interface, which is known as the positive-inside rule in membrane topology. The mechanism underlying the function of these charged residues remains poorly understood. Herein, we studied the function of cytoplasmic residues in corin, a type II transmembrane serine protease in cardiovascular biology. We found that the positively charged residue at the cytoplasm-membrane interface of corin was not a primary determinant in membrane topology but probably served as a charge-repulsion mechanism in the endoplasmic reticulum (ER) to prevent interactions with proteins in the ER, including the signal peptidase. Substitution of the positively charged residue with a neutral or acidic residue resulted in corin secretion likely due to signal peptidase cleavage. In signal peptidase-deficient cells, the mutant corin proteins were not secreted but retained in the ER. Similar results were found in the low-density lipoprotein receptor and matriptase-2 that have positively charged residues at and near the cytoplasm-membrane interface. These results provide important insights into the role of the positively charged cytoplasmic residues in mammalian single-pass transmembrane proteins. |
| format | Article |
| id | doaj-art-8d5c7580742d4cdb8760bf9ff1d0aefa |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-8d5c7580742d4cdb8760bf9ff1d0aefa2025-01-26T12:47:59ZengNature PortfolioCommunications Biology2399-36422025-01-018111310.1038/s42003-025-07545-7Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retentionHui Li0Shijin Sun1Wenjun Guo2Lina Wang3Zihao Zhang4Yue Zhang5Ce Zhang6Meng Liu7Shengnan Zhang8Yayan Niu9Ningzheng Dong10Qingyu Wu11Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityCyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Suzhou Medical College, Soochow UniversityAbstract Positively charged residues are commonly located near the cytoplasm-membrane interface, which is known as the positive-inside rule in membrane topology. The mechanism underlying the function of these charged residues remains poorly understood. Herein, we studied the function of cytoplasmic residues in corin, a type II transmembrane serine protease in cardiovascular biology. We found that the positively charged residue at the cytoplasm-membrane interface of corin was not a primary determinant in membrane topology but probably served as a charge-repulsion mechanism in the endoplasmic reticulum (ER) to prevent interactions with proteins in the ER, including the signal peptidase. Substitution of the positively charged residue with a neutral or acidic residue resulted in corin secretion likely due to signal peptidase cleavage. In signal peptidase-deficient cells, the mutant corin proteins were not secreted but retained in the ER. Similar results were found in the low-density lipoprotein receptor and matriptase-2 that have positively charged residues at and near the cytoplasm-membrane interface. These results provide important insights into the role of the positively charged cytoplasmic residues in mammalian single-pass transmembrane proteins.https://doi.org/10.1038/s42003-025-07545-7 |
| spellingShingle | Hui Li Shijin Sun Wenjun Guo Lina Wang Zihao Zhang Yue Zhang Ce Zhang Meng Liu Shengnan Zhang Yayan Niu Ningzheng Dong Qingyu Wu Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention Communications Biology |
| title | Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention |
| title_full | Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention |
| title_fullStr | Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention |
| title_full_unstemmed | Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention |
| title_short | Positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention |
| title_sort | positively charged cytoplasmic residues in corin prevent signal peptidase cleavage and endoplasmic reticulum retention |
| url | https://doi.org/10.1038/s42003-025-07545-7 |
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