Journal of Proteomics & Bioinformatics
Open Access

Modelling protein-protein interactions to elucidate molecular mechanism responsible for Ataxin-1 self-aggregation

14^th International Conference on Structural Biology

September 24-26, 2018 | Berlin, Germany

Gianvito Grasso

IDSIA, Switzerland

Posters & Accepted Abstracts: J Proteomics Bioinform

Abstract :

The worldwide significant increase in the life expectancy has recently drawn the attention of the scientific community to neurodegenerative pathologies of the elderly population. These neurodegenerative disorders arise from the abnormal protein aggregation in the nervous tissue leading to intracellular inclusions or extracellular aggregates in specific brain areas. Although the substantial research effort in this field, the fundamental mechanisms of protein misfolding remain somewhat unrevealed. The multiscale nature of the protein aggregation pathway requires investigation at multiple time and length scales to provide a deep understanding of molecular reasons responsible for the disease onset and severity. In this context, computational molecular modelling has often demonstrated to be a powerful tool in connecting macroscopic experimental findings to nanoscale molecular event. The present work aims at investigating molecular features of protein folding and proteinprotein interactions leading to protein aggregation in case of atax in-1 (ATX1), the protein responsible for spinocerebellar ataxia type-1. Despite poly glutamine expansion is an essential step in the disease onset, it is now established the leading role of AXH domain of ATX1, so far the only structured globular region identified along the protein sequence, in modulating the aggregation pathway. However, the AXH self-association mechanism is not yet clarified and several crucial questions remain open. The present work employs enhanced sampling techniques to fully characterize the AXH aggregation pathway from monomer to tetramer, identifying several protein mutations responsible for the destabilization of the monomer/dimer/ tetramer equilibrium. To address this goal, classical molecular dynamics together with enhanced sampling techniques have been employed to provide novel insights into the previously mentioned issues. Outcome of the present research represents the basis for a future design of aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.

Biography :