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MBC in Press, published online ahead of print November 12, 2008
Mol. Biol. Cell 10.1091/mbc.E08-08-0876

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Submitted on August 28, 2008
Revised on October 27, 2008
Accepted on November 5, 2008

Novel Findings on Uromodulin Polymerisation Provide New Insights into the Mechanisms Regulating ZP Domain-mediated Protein Assembly

Céline Schaeffer,* Sara Santambrogio,*{dagger} Simone Perucca,* Giorgio Casari,{ddagger} and Luca Rampoldi*

*Dulbecco Telethon Institute, Molecular Genetics of Renal Disorders, San Raffaele Scientific Institute, 20132 Milan, Italy; {ddagger}Human Molecular Genetics, San Raffaele Scientific Institute, 20132 Milan, Italy

Monitoring Editor: M. Bishr Omary

Uromodulin is the most abundant protein secreted in urine where it is found as a high molecular weight polymer. Polymerization occurs via its zona pellucida (ZP) domain, a conserved module shared by many extracellular eukaryotic proteins that are able to assemble into matrices. In this work, we identified two motifs in uromodulin, mapping in the linker region of the ZP domain and in between protein cleavage and GPI-anchoring sites, which regulate its polymerization. Indeed, mutations in either module led to premature intracellular polymerization of a soluble uromodulin isoform demonstrating the inhibitory role of these motifs for ZP domain-mediated protein assembly. Proteolytic cleavage separating the external motif from the mature monomer is necessary to release the inhibitory function and allow protein polymerization. Moreover, we report absent or abnormal assembly into filaments of GPI-anchored uromodulin mutated in either the internal or the external motif. This effect is due to altered processing on the plasma membrane demonstrating that the presence of the two modules has not only an inhibitory function but can also positively regulate protein polymerization. Our data expand previous knowledge on the control of ZP domain function and suggest a common mechanism regulating polymerization of ZP domain proteins.

{dagger}Present address: Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.

Address correspondence to: Luca Rampoldi (rampoldi.luca{at}hsr.it)






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