Prediction of Co-Translational Protein Folding in Living Cells

Abstract

Protein folding, the self-assembly of a protein molecule or domain into a tertiary structure, can occur as a protein molecule is being synthesized by the ribosome in a process referred to as co-translational folding. The most convincing demonstration that co-translational folding occurs inside cells comes from pulse-chase experiments in which the synthesis of the cytosolic Semliki Forest virus protein (SFVP) was monitored in Chinese hamster ovarian cells [1]. SFVP is composed of four distinct protein segments, including an N-terminal protease segment (referred to as “C protein”) that auto-catalytically cleaves itself from the SFVP molecule once folded. The pulse-chase experiment revealed that the cleaved C protein appeared well before synthesis of the full-length SFVP was completed, demonstrating that C protein does indeed fold co-translationally in vivo. Here, we show that the time course of such co-translational folding can be accurately predicted by a chemical kinetic model using a domain's bulk folding and unfolding rates and the average rate at which codons are translated in vivo; such quantities have been reported in the literature for a number of different proteins and cell types, suggesting this theoretical approach can be applied to a wide variety of proteins. The model explains the essential features of co-translational folding time courses, and provides a means for predicting how varying the translation rate at different codon positions along a transcript's open reading frame affects this self-assembly process in vivo.[1] Nicola, A. V., Chen, W. & Helenius, A. Co-translational folding of an alphavirus capsid protein in the cytosol of living cells. Nat. Cell Biol. 1, 341-5 (1999).