Structural Basis of Highly Specific Interaction between Nephrin and MAGI1 in Slit Diaphragm Assembly and Signaling | |
Shang, Yuan1,4; Weng, Zhuangfeng1,2; Lin, Lin2; Zhang, Rongguang2,3; Zhu, Jinwei2; Ji, Zeyang4; Ye, Fei4,5 | |
刊名 | JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY |
2018 | |
卷号 | 29期号:9页码:2362-2371 |
关键词 | Congenital Nephrotic Syndrome Focal Segmental Glomerulosclerosis Proteins Mutations Podocytes Complex Filtration Membrane Adhesion Disease |
ISSN号 | 1046-6673 |
DOI | 10.1681/ASN.2017121275 |
文献子类 | Article |
英文摘要 | Background The slit diaphragm is a specialized adhesion junction between opposing podocytes, establishing the final filtration barrier that prevents passage of proteins from the capillary lumen into the urinary space. Nephrin, the key structural and signaling adhesion molecule expressed in the slit diaphragm, contains an evolutionally conserved, atypical PDZ-binding motif (PBM) reported to bind to a variety of proteins in the slit diaphragm. Several mutations in NPHS1 (the gene encoding nephrin) that result in nephrin lacking an intact PBM are associated with glomerular diseases. However, the molecular basis of nephrin-PBM-mediated protein complexes is still unclear. Methods Using a combination of biochemic, biophysic, and cell biologic approaches, we systematically investigated the interactions between nephrin-PBM and PDZ domain-containing proteins in the slit diaphragm. Results We found that nephrin-PBM specifically binds to one member of the membrane-associated guanylate kinase family of scaffolding proteins, MAGI1, but not to another, MAGI2. The complex structure of MAGI1-PDZ3/nephrin-PBM reveals that the Gly at the -3 position of nephrin-PBM is the determining feature for MAGI1-PDZ3 recognition, which sharply contrasts with the typical PDZ/PBM binding mode. A single gain-of-function mutation within MAGI2 enabled nephrin-PBM binding. In addition, using our structural analysis, we developed a highly efficient inhibitory peptide capable of specifically blocking the nephrin/MAGI1 interaction. Conclusions MAGI1 interacts with nephrin-PBM with exquisite specificity. A newly developed, potent inhibitory peptide that blocks this interaction may be useful for future functional investigations in vivo. Our findings also provide possible explanations for the diseases caused by NPHS1 mutations. |
电子版国际标准刊号 | 1533-3450 |
WOS研究方向 | Urology & Nephrology |
语种 | 英语 |
WOS记录号 | WOS:000449014200012 |
内容类型 | 期刊论文 |
版本 | 出版稿 |
源URL | [http://202.127.25.143/handle/331003/3476] |
专题 | 生化所2018年发文 上海生化细胞研究所_上海生科院生化细胞研究所 |
通讯作者 | Zhang, Rongguang; Zhu, Jinwei |
作者单位 | 1.Univ Arizona, Ctr Biomed Informat & Biostat, Tucson, AZ USA; 2.Univ Chinese Acad Sci, Chinese Acad Sci, Ctr Excellence Mol Cell Sci,Shanghai Sci Res Ctr, State Key Lab Mol Biol,Shanghai Inst Biochem & Ce, Shanghai, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; 4.Hong Kong Univ Sci & Technol, State Key Lab Mol Neurosci, Div Life Sci, Kowloon, Hong Kong, Peoples R China; 5.Hong Kong Univ Sci & Technol, Ctr Syst Biol & Human Hlth, Kowloon, Hong Kong, Peoples R China |
推荐引用方式 GB/T 7714 | Shang, Yuan,Weng, Zhuangfeng,Lin, Lin,et al. Structural Basis of Highly Specific Interaction between Nephrin and MAGI1 in Slit Diaphragm Assembly and Signaling[J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY,2018,29(9):2362-2371. |
APA | Shang, Yuan.,Weng, Zhuangfeng.,Lin, Lin.,Zhang, Rongguang.,Zhu, Jinwei.,...&Ye, Fei.(2018).Structural Basis of Highly Specific Interaction between Nephrin and MAGI1 in Slit Diaphragm Assembly and Signaling.JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY,29(9),2362-2371. |
MLA | Shang, Yuan,et al."Structural Basis of Highly Specific Interaction between Nephrin and MAGI1 in Slit Diaphragm Assembly and Signaling".JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 29.9(2018):2362-2371. |
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