Small molecule modulators of α-synuclein toxicity in a yeast model

Abstract

Gene encodes linear sequence of nucleotides that specify amino acids attached through peptide bond in a head to tail fashion. Christian B. Anfinson (1954) postulated that information for a protein to fold in a three-dimensional structure provided from a one dimensional amino acid sequence. A protein has to fold properly to attain correct minimal-energy configuration to arrive at its native, functional form. This process occurs in micro- to nano- seconds. Levinthal (1968) stated that protein rapidly folds through nearby amino acids interaction, thus limiting the available conformational space. Protein folding follows a funnel-shaped energy landscape to attain the minimal energy and most stable confirmation. Often protein folds in a co-translational manner, while others in specific compartments like ER fold after trafficking and translocation through its membrane. Protein misfolding is one of the common events occurring in a cell. Protein misfolding occurs when a protein cannot fold into its native form primarily due to aggregation propensity of amino acid sequences. Molecular chaperones help the proteins that have difficulty in attaining their native state. Often accumulations of misfolded proteins are checked by cellular proteastatic machineries. Due to disturbance in the fine balance between generation and degradation of misfolded proteins, it starts building up and burdens the protein quality control system which eventually reduces its efficacy. Misfolded proteins convert to toxic aggregates by the widely accepted “Nuclear growth model” (Vendruscolo M et al., 2011).