1. Re: A Structured Interdomain Linker Directs Self-Polymerization of Human Uromodulin
- Author
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Luca Rampoldi, Luca Jovine, K. Nishimura, Martina Brunati, Ling Han, Marcel Bokhove, Daniele de Sanctis, Bokhove, M, Nishimura, K, Brunati, M, Han, L, de Sanctis, D, Rampoldi, L, Jovine, L, Karolinska Inst, Ctr Innovat Med, SE-14183 Huddinge, Sweden, Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden, Ist Sci San Raffaele, Div Genet & Cell Biol, Mol Genet Renal Disorders Unit, I-20132 Milan, Italy, and European Synchrotron Radiation Facility (ESRF)
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Models, Molecular ,0301 basic medicine ,Tamm–Horsfall protein ,[SDV]Life Sciences [q-bio] ,030232 urology & nephrology ,Fluorescent Antibody Technique ,Crystallography, X-Ray ,Madin Darby Canine Kidney Cells ,Polymerization ,Mice ,0302 clinical medicine ,Medicine ,Disulfides ,TECTA ,chemistry.chemical_classification ,Extracellular Matrix Proteins ,education.field_of_study ,Multidisciplinary ,biology ,Sperm receptor ,Biological Sciences ,Cell biology ,Biochemistry ,ZP2 ,Recombinant Fusion Proteins ,Urology ,Blotting, Western ,Molecular Sequence Data ,Mutation, Missense ,Computational biology ,GPI-Linked Proteins ,Maltose-Binding Proteins ,03 medical and health sciences ,Dogs ,Uromodulin ,Animals ,Humans ,Amino Acid Sequence ,education ,Gene ,X-ray crystallography ,Innate immune system ,zona pellucida domain ,business.industry ,Protein Structure, Tertiary ,HEK293 Cells ,030104 developmental biology ,chemistry ,Structural Homology, Protein ,biology.protein ,Protein Multimerization ,Glycoprotein ,business ,Sequence Alignment ,Linker ,030217 neurology & neurosurgery ,Function (biology) - Abstract
International audience; Uromodulin (UMOD)/Tamm-Horsfall protein, the most abundant human urinary protein, plays a key role in chronic kidney diseases and is a promising therapeutic target for hypertension. Via its bipartite zona pellucida module (ZP-N/ZP-C), UMOD forms extracellular filaments that regulate kidney electrolyte balance and innate immunity, as well as protect against renal stones. Moreover, salt-dependent aggregation of UMOD filaments in the urine generates a soluble molecular net that captures uropathogenic bacteria and facilitates their clearance. Despite the functional importance of its homopolymers, no structural information is available on UMOD and how it self-assembles into filaments. Here, we report the crystal structures of polymerization regions of human UMOD and mouse ZP2, an essential sperm receptor protein that is structurally related to UMOD but forms heteropolymers. The structure of UMOD reveals that an extensive hydrophobic interface mediates ZP-N domain homodimerization. This arrangement is required for filament formation and is directed by an ordered ZP-N/ZP-C linker that is not observed in ZP2 but is conserved in the sequence of deafness/Crohn's disease-associated homopolymeric glycoproteins a-tectorin (TECTA) and glycoprotein 2 (GP2). Our data provide an example of how interdomain linker plasticity can modulate the function of structurally similar multidomain proteins. Moreover, the architecture of UMOD rationalizes numerous pathogenic mutations in both UMOD and TECTA genes
- Published
- 2016
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