11.1 STIR: Multi-level Hidden Markov Model for Co-translational Protein Targeting
Abstract
To maintain proper cellular function, over 50% of all proteins encoded in the genome need to be transported through or in cellular membranes. Co-translational protein targeting is such a process in which proteins still being synthesized on the ribosome are transported through the endoplasmic reticulum membrane. The correct transportation of the unfolded proteins and the subsequent folding, assembly and quality control play a critical role in the healthy function of cells and organs. Improper co-translational protein translocation and/or the subsequent protein processing causes numerous diseases. It is also known that protein toxins use retrotranslocationÐthe reserve of normal protein transportÐto enter the cytoplasm of the target cell. Despite the biological significance, the detailed molecular mechanism behind the co-translational protein targeting process is not well understood. The aim of this research is to build mathematical models to investigate the unsolved questions regarding the molecular mechanism of the co-translational protein targeting process. This research involves three main tasks: 1) Build a novel multi-level hidden Markov model for the conformational dynamics of the molecular complexes that govern the protein targeting process. This multi-level modeling allows the combination and extraction of information from multiple proteins for a deeper understanding of the molecular mechanism at work. 2) Employ the multi-level hidden Markov model to account for the stochastic heterogeneity among the multiple proteins, which is necessary for detailed molecular understanding of the co-translational protein targeting process. 3) Apply the multi-level hidden Markov model to recent single-molecule experimental data on bacterial protein targeting systems. Direct fitting to the biological data not only gives the experimental assessment of the model, but also allows us to extract experimental information in combination with our mathematical model to elucidate the detailed molecular mechanism of protein targeting.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 12, 2017
- Source ID
- W911NF1610286
Entities
People
- Shingchang Kou
Organizations
- Army Contracting Command
- Harvard University
- United States Army