15 Luglio 2103

articolo postato il: 2013-07-19 23:33:49

TRiC`s tricks inhibit huntingtin aggregation.

Shahmoradian SH, Galaz-Montoya JG, Schmid MF, Cong Y, Ma B, Spiess C, Frydman J, Ludtke SJ, Chiu W.

Elife. 2013 Jul 9;2:e00710. doi: 10.7554/eLife.00710.

 

Un articolo molto bello, questa settimana su una rivista online molto dinamica ed efficiente (Elife) in cui si  descrive il meccanismo molecolare di una "chaperone" intracellulare (TRIC) nell`inibizione dell` aggregazione di Huntingtina. Vale la pena di leggerlo anche solo per godere le immagini stupende ottenute con cryo-EM. 

Si sta rivelando uno scenario in cui sembra che le "chaperone" agiscano sulla inibizione della fibrillogenesi in modo eterogeneo (alta affinità, bassa affinità, con il riconoscimento solo del precursore native-like  o il riconoscimento sia del precursore che delle fibrille).

 

 

Abstract

In Huntington`s disease, a mutated version of the huntingtin protein leads to cell death. Mutant huntingtin is known to aggregate, a process that can be inhibited by the eukaryotic chaperonin TRiC (TCP1-ring complex) in vitro and in vivo. A structural understanding of the genesis of aggregates and their modulation by cellular chaperones could facilitate the development of therapies but has been hindered by the heterogeneity of amyloid aggregates. Using cryo-electron microscopy (cryoEM) and single particle cryo-electron tomography (SPT) we characterize the growth of fibrillar aggregates of mutant huntingtin exon 1 containing an expanded polyglutamine tract with 51 residues (mhttQ51), and resolve 3-D structures of the chaperonin TRiC interacting with mhttQ51. We find that TRiC caps mhttQ51 fibril tips via the apical domains of its subunits, and also encapsulates smaller mhtt oligomers within its chamber. These two complementary mechanisms provide a structural description for TRiC`s inhibition of mhttQ51 aggregation in vitro.