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Combination of hydrophobicity and codon usage bias determines sorting of model K+ channel protein to either mitochondria or endoplasmic reticulum
Authors:Anja J Engel  Steffen Paech  Markus Langhans  James L van Etten  Anna Moroni  Gerhard Thiel  Oliver Rauh
Institution:1. Faculty of Biology, Technical University of Darmstadt, Darmstadt, Germany;2. Faculty of Chemistry, Macromolecular and Paper Chemistry, Technical University of Darmstadt, Darmstadt, Germany;3. Department of Plant Pathology and Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA;4. Department of Biosciences and CNR IBF-Mi, Università degli Studi di Milano, Milan, Italy
Abstract:When the K+ channel-like protein Kesv from Ectocarpus siliculosus virus 1 is heterologously expressed in mammalian cells, it is sorted to the mitochondria. This targeting can be redirected to the endoplasmic reticulum (ER) by altering the codon usage in distinct regions of the gene or by inserting a triplet of hydrophobic amino acids (AAs) into the protein's C-terminal transmembrane domain (ct-TMD). Systematic variations in the flavor of the inserted AAs and/or its codon usage show that a positive charge in the inserted AA triplet alone serves as strong signal for mitochondria sorting. In cases of neutral AA triplets, mitochondria sorting are favored by a combination of hydrophilic AAs and rarely used codons; sorting to the ER exhibits the inverse dependency. This propensity for ER sorting is particularly high when a common codon follows a rarer one in the AA triplet; mitochondria sorting in contrast is supported by codon uniformity. Since parameters like positive charge, hydrophobic AAs, and common codons are known to facilitate elongation of nascent proteins in the ribosome the data suggest a mechanism in which local changes in elongation velocity and co-translational folding in the ct-TMD influence intracellular protein sorting.
Keywords:codon usage  effect of synonymous codon exchange  membrane protein sorting  transmembrane domain hydrophobicity
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