1t3s

From Proteopedia

---

Revision as of 00:50, 21 November 2007

proteopedia linkproteopedia link

spinqualitylabelsall models 1t3s, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Structural Analysis of the Voltage-Dependent Calcium Channel Beta Subunit Functional Core

Overview

Huntington's disease (HD) is initiated by an abnormally expanded, polyglutamine stretch in the huntingtin protein, conferring a novel, property on the protein that leads to the loss of striatal neurons., Defects in mitochondrial function have been implicated in the pathogenesis, of HD. Here, we have examined the hypothesis that the mutant huntingtin, protein may directly interact with the mitochondrion and affect its, function. In human neuroblastoma cells and clonal striatal cells, established from HdhQ7 (wild-type) and HdhQ111 (mutant) homozygote mouse, knock-in embryos, huntingtin was present in a purified mitochondrial, fraction. Subfractionation of the mitochondria and limited trypsin, digestion of the organelle demonstrated that huntingtin was associated, with the outer mitochondrial membrane. We further demonstrated that a, recombinant truncated mutant huntingtin protein, but not a wild-type, directly induced mitochondrial permeability transition (MPT) pore opening, in isolated mouse liver mitochondria, an effect that was prevented, completely by cyclosporin A (CSA) and ATP. Importantly, the mutant, huntingtin protein significantly decreased the Ca2+ threshold necessary to, trigger MPT pore opening. We found a similar increased susceptibility to, the calcium-induced MPT in liver mitochondria isolated from a knock-in HD, mouse model. The mutant huntingtin protein-induced MPT pore opening was, accompanied by a significant release of cytochrome c, an effect completely, inhibited by CSA. These findings suggest that the development of specific, MPT inhibitors may be an interesting therapeutic avenue to delay the onset, of HD.

About this Structure

1T3S is a Single protein structure of sequence from Oryctolagus cuniculus with HG as ligand. Full crystallographic information is available from OCA.

Reference

Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release., Choo YS, Johnson GV, MacDonald M, Detloff PJ, Lesort M, Hum Mol Genet. 2004 Jul 15;13(14):1407-20. Epub 2004 May 26. PMID:15163634

Page seeded by OCA on Wed Nov 21 02:58:02 2007