Evidence of Evolutionary Constraints That Influences the Sequence Composition and Diversity of Mitochondrial Matrix Targeting Signals

Stephen R Doyle,Warwick N Grant,Chee Kai Chan,Naga R P Kasinadhuni,Niall James Haslam

doi:10.1371/journal.pone.0067938

Abstract

Mitochondrial targeting signals (MTSs) are responsible for trafficking nuclear encoded proteins to their final destination within mitochondria. These sequences are diverse, sharing little amino acid homology and vary significantly in length, and although the formation of a positively-charged amphiphilic alpha helix within the MTS is considered to be necessary and sufficient to mediate import, such a feature does not explain their diversity, nor how such diversity influences target sequence function, nor how such dissimilar signals interact with a single, evolutionarily conserved import mechanism. An in silico analysis of 296 N-terminal, matrix destined MTSs from Homo sapiens, Mus musculus, Saccharomyces cerevisiae, Arabidopsis thaliana, and Oryza sativa was undertaken to investigate relationships between MTSs, and/or, relationships between an individual targeting signal sequence and the protein that it imports. We present evidence that suggests MTS diversity is influenced in part by physiochemical and N-terminal characteristics of their mature sequences, and that some of these correlated characteristics are evolutionarily maintained across a number of taxa. Importantly, some of these associations begin to explain the variation in MTS length and composition.

Highlights

It is generally accepted that mitochondria have evolved from an alpha-proteobacterium that was engulfed by an ancestral eukaryotic cell over one billion years ago
This list was comprised of two mammalian species, H. sapiens (85 sequences) and M. musculus (84), the bakers yeast S. cerevisiae (56), and two plant species, the monocot O. sativa (36) and the dicot A. thaliana (35)
The primary amino acid sequence for each protein was divided into two sequences (MTS and the mature sequence), after which a range of sequence properties was determined for each Mitochondrial targeting signals (MTSs)/mature protein pair

Summary

Introduction

It is generally accepted that mitochondria have evolved from an alpha-proteobacterium that was engulfed by an ancestral eukaryotic cell over one billion years ago. The gradual loss of autonomy to the nucleus would have required a number of independent events to occur [1,2]: the transfer and integration of bacterial-derived genetic information into the nuclear genome, followed by genetic modifications to allow nuclear transcription and regulation, translation on cytoplasmic ribosomes and lastly, trafficking of the protein to its correct destination within the mitochondria This trafficking process is mediated by multiple molecular interactions between the import apparatus and a mitochondrial targeting signal (MTS) sequence, a ‘molecular address’ that facilitates import and sorting to its correct destination (see Chacinska et al, [3], Mokranjac and Neupert [4] and Schleiff and Becker [5] for comprehensive descriptions of the import pathway). MTSs from different proteins share virtually no sequence homology and vary extensively in length; proteins targeted to the mitochondrial matrix do typically contain an N-

Methods

Results

Conclusion