1iii

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spinqualitylabelsall models 1iii, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF THE TRANSTHYRETIN MUTANT TTR Y114C-DATA COLLECTED AT ROOM TEMPERATURE

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The Y114C mutation in human transthyretin (TTR) is associated with a, particular form of familial amyloidotic polyneuropathy. We show that, vitreous aggregates ex vivo consist of either regular amyloid fibrils or, disordered disulfide-linked precipitates that maintain the ability to bind, Congo red. Furthermore, we demonstrate in vitro that the ATTR Y114C mutant, exists in three forms: one unstable but nativelike tetrameric form, one, highly aggregated form in which a network of disulfide bonds is formed, and one fibrillar form. The disulfide-linked aggregates and the fibrillar, form of the mutant can be induced by heat induction under nonreduced and, reduced conditions, respectively. Both forms are recognized by the amyloid, specific antibody MAB(39-44). In a previous study, we have linked exposure, of this epitope in TTR to a three-residue shift in beta-strand D. The, X-ray crystallographic structure of reduced tetrameric ATTR Y114C shows a, structure similar to that of the wild type but with a more buried position, of Cys10 and with beta-mercaptoethanol associated with Cys114, verifying, the strong tendency for this residue to form disulfide bonds. Combined, with the ex vivo data, our in vitro findings suggest that ATTR Y114C can, lead to disease either by forming regular unbranched amyloid fibrils or by, forming disulfide-linked aggregates that maintain amyloid-like properties, but are unable to form regular amyloid fibrils.

Disease

Known diseases associated with this structure: Amyloid neuropathy, familial, several allelic types OMIM:[176300], Amyloidosis, senile systemic OMIM:[176300], Carpal tunnel syndrome, familial OMIM:[176300], Dystransthyretinemic hyperthyroxinemia OMIM:[176300]

About this Structure

1III is a Single protein structure of sequence from Homo sapiens with BME as ligand. Full crystallographic information is available from OCA.

Reference

Disulfide-bond formation in the transthyretin mutant Y114C prevents amyloid fibril formation in vivo and in vitro., Eneqvist T, Olofsson A, Ando Y, Miyakawa T, Katsuragi S, Jass J, Lundgren E, Sauer-Eriksson AE, Biochemistry. 2002 Nov 5;41(44):13143-51. PMID:12403615

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