Predicting the protein half-life in tissue from its cellular properties.

Abstract

Protein half-life is an important feature of protein homeostasis (proteostasis). The increasing number of in vivo and in vitro studies using high throughput proteomics provide estimates of the protein half-lives in tissues and cells. However, protein half-lives in cells and tissues are different. Due to the resource requirements for researching tissues, more data is available from cellular studies than tissues. We have designed a multivariate linear model for predicting protein half-life in tissue from its cellular properties. Inputs to the model are cellular half-life, abundance, intrinsically disordered sequences, and transcriptional and translational rates. Before the modeling, we determined substructures in the data using the relative distance from the regression line of the protein half-lives in tissues and cells, identifying three separate clusters. The model was trained on and applied to predict protein half-lives from murine liver, brain and heart tissues. In each tissue type we observed similar prediction patterns of protein half-lives. We found that the model provides the best results when there is a strong correlation between tissue and cell culture protein half-lives. Additionally, we clustered the protein half-lives to determine variations in correlation coefficients between the protein half-lives in the tissue versus in cell culture. The clusters identify strongly and weakly correlated protein half-lives, further improves the overall prediction and identifies sub groupings which exhibit specific characteristics. The model described herein, is generalizable to other data sets and has been implemented in a freely available R code.