A regional net charge and structural compensation model to explain how negatively charged amino acids can be accepted within a mitochondrial leader sequence.
Mitochondrial leader sequences have been found to be statistically enriched for positively charged residues, with only a few known leader sequences possessing negatively charged residues. Mutational studies that have introduced negatively charged residues into various leader sequences have shown a general, but not absolute, trend toward reduced import. The leader sequence of rat liver aldehyde dehydrogenase has been previously determined by NMR to form a helix-linker-helix structure. A negative charge introduced into this leader did not prevent import, provided that a net positive charge remained in the N-helical segment. When the net charge of the N-terminal helical segment was reduced to zero, import could be recovered by removing the linker, which resulted in a longer, more stable leader. This structural recovery of import was effective enough to compensate for a net charge of zero within the first 10 residues, even when a glutamate is the first charged side chain presented in the sequence.
Heard
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Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907-1153, USA.
Weiner
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D000444:Aldehyde Dehydrogenase / Q000737:chemistry* / Q000235:genetics; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D002942:Circular Dichroism; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008930:Mitochondria, Liver / Q000737:chemistry* / Q000201:enzymology; D008958:Models, Molecular; D021382:Protein Sorting Signals / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D000596:Amino Acids; D004792:Enzyme Precursors; D021382:Protein Sorting Signals; D000444:Aldehyde Dehydrogenase