Structural insights into a zinc-dependent pathway leading to Leu55Pro transthyretin amyloid fibrils.

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Castro-Rodrigues AF, Gales L, Saraiva MJ, Damas AM

Structural insights into a zinc-dependent pathway leading to Leu55Pro transthyretin amyloid fibrils.

Acta Crystallogr D Biol Crystallogr. 2011 Dec;67(Pt 12):1035-44. doi: 10.1107/S090744491104491X. Epub 2011 Nov 5.

PubMed ID

22120741 [ View in PubMed

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Abstract

Human transthyretin (TTR) is a homotetrameric protein that is responsible for the formation of amyloid in patients with familiar amyloidotic polyneuropathy (FAP), familiar amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA). Amyloid fibrils are characterized by a cross-beta structure. However, details of how TTR monomers are organized to form such an assembly remain unknown. The effect of Zn(2+) in increasing TTR L55P amyloidogenecity has been reported. Crystals of the TTR L55P-Zn(2+) complex were grown under conditions similar to those leading to higher amyloidogenic potential of the variant protein and the three-dimensional structure of the complex was determined by X-ray crystallography. Two different tetrahedral Zn(2+)-binding sites were identified: one cross-links two tetramers, while the other lies at the interface between two monomers in a dimer. The association of monomers involving the two Zn(2+)-binding sites leads to a bidimensional array with a cross-beta structure. The formation of this structure and subsequent organization into amyloid fibrils was monitored by fluorescence spectroscopy and electron microscopy. The TTR L55P-Zn(2+) structure offers the first molecular insights into the role of Zn(2+) as a mediator of cross-beta-type structure in TTR amyloidosis and the relevance of a Zn(2+)-dependent pathway leading to the production of early amyloidogenic intermediates is discussed.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Zinc chloride	Transthyretin	Protein	Humans	Unknown	Inducer	Details
Zinc sulfate, unspecified form	Transthyretin	Protein	Humans	Unknown	Inducer	Details