5N7C

Human TTR altered conformation from soaking in CuCl2.

Summary for 5N7C

• Entry DOI: 10.2210/pdb5n7c/pdb
• Related: 5K1J 5K1N 5N5Q 5N62
• Descriptor: Transthyretin, COPPER (II) ION, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: copper ttr complex, metal binding, alzheimer beta-amyloid scavenging, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 26340.89

Authors

Ciccone, L.,Savko, M.,Shepard, W.,Stura, E.A. (deposition date: 2017-02-20, release date: 2018-03-14, Last modification date: 2024-01-17)

Primary citation

Ciccone, L.,Fruchart-Gaillard, C.,Mourier, G.,Savko, M.,Nencetti, S.,Orlandini, E.,Servent, D.,Stura, E.A.,Shepard, W.
Copper mediated amyloid-beta binding to Transthyretin.
Sci Rep, 8:13744-13744, 2018

PubMed Abstract: Transthyretin (TTR), a homotetrameric protein that transports thyroxine and retinol both in plasma and in cerebrospinal (CSF) fluid provides a natural protective response against Alzheimer's disease (AD), modulates amyloid-β (Aβ) deposition by direct interaction and co-localizes with Aβ in plaques. TTR levels are lower in the CSF of AD patients. Zn, Mn and Fe transform TTR into a protease able to cleave Aβ. To explain these activities, monomer dissociation or conformational changes have been suggested. Here, we report that when TTR crystals are exposed to copper or iron salts, the tetramer undergoes a significant conformational change that alters the dimer-dimer interface and rearranges residues implicated in TTR's ability to neutralize Aβ. We also describe the conformational changes in TTR upon the binding of the various metal ions. Furthermore, using bio-layer interferometry (BLI) with immobilized Aβ(1-28), we observe the binding of TTR only in the presence of copper. Such Cu-dependent binding suggests a recognition mechanism whereby Cu modulates both the TTR conformation, induces a complementary Aβ structure and may participate in the interaction. Cu-soaked TTR crystals show a conformation different from that induced by Fe, and intriguingly, TTR crystals grown in presence of Aβ(1-28) show different positions for the copper sites from those grown its absence.

PubMed: 30213975
DOI: 10.1038/s41598-018-31808-5

Experimental method

X-RAY DIFFRACTION (2.45 Å)