Alteration of protein subcellular location and domain formation by alternative translational initiation

Abstract

Alternative translation is an important cellular mechanism contributing to the generation of proteins and the diversity of protein functions. Instead of studying individual cases, we systematically analyzed the alteration of protein subcellular location and domain formation by alternative translational initiation in eukaryotes. The results revealed that 85.7% of alternative translation events generated biological diversity, attributed to different subcellular localizations and distinct domain contents in alternative isoforms. Analysis of isoelectric point values revealed that most N-terminal truncated isoforms significantly lowered their isoelectric point values targeted at different subcellular localizations, whereas they had conserved domain contents the same as the full-length isoforms. Furthermore, Fisher's exact test indicated that the two ways-targeting at different cellular compartments and changing domain contents-were negatively associated. The N-term truncated isoforms should have only one way to diversify their functions distinct from the full-length ones. The peculiar consequence of subcellular relocation as well as change of domain contents reflected the very high level of biological complexity as alternative usage of initiation codons.

N-terminal Proteomics and Ribosome Profiling Provide a Comprehensive View of the Alternative Translation Initiation Landscape in Mice and Men

“…Overall, the TargetP output strengthens the idea that dTIS usage has an impact on protein subcellular localization (35)(36)90), which was also hypothesized and computationally investigated by Cai et al (91) and in fact proven for a variety of N-terminal protein isoforms generated by means of alternative translation initiation. Table S1), thereby providing evidence that these represent genuine translation initiation sites in mouse and human transcripts (22), and thus that these N termini are representative for N-terminal protein variants.…”

N-terminal Isoforms of the Large-conductance Ca2+-activated K+ Channel Are Differentially Modulated by the Auxiliary β1-Subunit

“…Alternative translation initiation has been described to modulate the expression and function of N-terminal truncated forms of certain potassium channels: the voltage-gated potassium channel Kv3.3 (38) and the two P-domain potassium channels K 2P 2.1 and K 2P 10.1 (39,40). Alternative translation initiation is a mechanism to regulate protein diversity whereby proteins with different N termini are produced from a single mRNA (41). Alternative translation initiation occurs during translation when the ribosome binds to an initiation codon (AUG) that is not the first cap-proximal in the mRNA coding region, thereby generating N-terminally truncated protein isoforms.…”

Alternative translation start sites and hidden coding potential of eukaryotic mRNAs

“…(67,70,73) Thus, it is likely that some N-end heterogeneity resulting from the alternative translation and a dual (or multiple) localization are the characteristic feature of many eukaryotic proteins. (74,75) Protein isoforms localized in different compartments may be synthesized in very different amounts, and this disequilibrium could mask some of them from detection by standard proteomic techniques. New methods for detection of such minor isoforms (location-specific depletion or subcellular knockout) were recently developed.…”