Survey of Potential Regulatory Roles for -1 Programmed Ribosomal Frameshifting within the Human Proteome
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Alphaviruses have developed mechanisms to expand the coding capacity of their genome through a process called programmed ribosomal frameshifting (PRF). PRF allows for translation to proceed in an alternative reading frame in order to create two proteins from a single transcript. Negative 1PRF in the alphavirus polyprotein generates the transframe protein (TF), which is important for the virulence of alphaviruses. If the virus is able to thrive using PRF, this is detrimental to the organism in direct contact. Through biochemical analysis of the Sindbis virus structural polyprotein, it was found that the innate cause of the -1 PRF is translocon-mediated membrane integration of a hydrophobic transmembrane domain. This process triggers a pull on the ribosome that causes it to slip into the -1-reading frame. Results show the efficiency of -1 PRF is dependent on the hydrophobicity of this transmembrane domain. Using this information, we carried out a bioinformatic search for proteins containing comparable sequences within the human proteome. Previous results reveal hundreds of human proteins contain this motif, suggesting -1PRF may impact human gene misfolding. Using cellular and biochemical techniques, the present study focuses on the development of a model system allowing for future evaluation of PRF and how it shapes the translation of SCN5a and SLC35a genes.