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1 Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, USA
2 U538, Institut National de la Sante et de la Recherche Medicale, Paris, France
3 Genetics, University of Barcelona, Barcelona, Spain
4 Nephrology/Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA; Research, VA Medical Center, New Orleans, LA, USA
* To whom correspondence should be addressed. E-mail: bklassen{at}xula.edu.
Although several heavy metal toxins are delivered to the kidney on the carrier protein metallothionein, uncertainty as to how metallothionein enters proximal tubular cells limits treatment strategies. Prompted by reports that metallothionein-I (MT) interferes with renal
uptake of the megalin ligand 
2-microglobulin in conscious rats, we tested the hypothesis that megalin binds MT and mediates its uptake. Three lines of evidence suggest binding of MT to megalin is critical in renal proximal tubular uptake of MT-bound heavy metals. First, MT binds megalin but not cubilin in direct surface plasmon resonance studies. Binding of MT occurs at a
single site with Kd ~ 10-4 and, as with other megalin ligands, depends on divalent cations. Second, antisera and various known megalin ligands inhibit the uptake of fluorescently labeled MT in model cell systems. Anti-megalin antisera, but not control sera, displace >90% bound MT from rat renal brush border membranes. Megalin ligands including 2-microglobulin and also recombinant MT fragments compete for uptake by megalin-expressing rat yolk sac BN-16 cells.
Third, megalin and fluorescently labeled MT colocalize in BN-16 cells, as shown by fluorescent microscopy techniques. Follow-up surface plasmon resonance and flow cytometry studies using overlapping MT peptides and recombinant MT fragments identify the hinge SCKKSCC region of MT as a critical site for megalin binding. These findings suggest disruption of the SCKKSCC motif can inhibit proximal tubular MT uptake and thereby eliminate much of the renal
accumulation and toxicity of heavy metals such as cadmium, gold, copper and cisplatinum.
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