Human metallothioneins 2 and 3 differentially affect amyloid-beta binding by transthyretin.
Transthyretin (TTR), an amyloid-beta (Abeta) scavenger protein, and metallothioneins 2 and 3 (MT2 and MT3), low molecular weight metal-binding proteins, have recognized impacts in Abeta metabolism. Because TTR binds MT2, an ubiquitous isoform of the MTs, we investigated whether it also interacts with MT3, an isoform of the MTs predominantly expressed in the brain, and studied the role of MT2 and MT3 in human TTR-Abeta binding. The TTR-MT3 interaction was characterized by yeast two-hybrid assays, saturation-binding assays, co-immunolocalization and co-immunoprecipitation. The effect of MT2 and MT3 on TTR-Abeta binding was assessed by competition-binding assays. The results obtained clearly demonstrate that TTR interacts with MT3 with a K(d) of 373.7 +/- 60.2 nm. Competition-binding assays demonstrated that MT2 diminishes TTR-Abeta binding, whereas MT3 has the opposite effect. In addition to identifying a novel ligand for TTR that improves human TTR-Abeta binding, the present study highlights the need to clarify whether the effects of MT2 and MT3 in human TTR-Abeta binding observed in vitro have a relevant impact on Abeta deposition in animal models of Alzheimer's disease.
Martinho
Ana
A
Health Sciences Research Centre, CICS, University of Beira Interior, Covilhã, Portugal.
Gonçalves
Isabel
I
Cardoso
Isabel
I
Almeida
Maria R
MR
Quintela
Telma
T
Saraiva
Maria J
MJ
Santos
Cecília R A
CR
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D008668:Metallothionein / Q000378:metabolism*; D000090023:Metallothionein 3; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011228:Prealbumin / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D020798:Two-Hybrid System Techniques
D016229:Amyloid beta-Peptides; D006131:Growth Inhibitors; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D011228:Prealbumin; D008668:Metallothionein