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J Biol Chem, Vol. 273, Issue 45, 29389-29393, November 6, 1998

A Regional Net Charge and Structural Compensation Model to Explain How Negatively Charged Amino Acids Can Be Accepted within a Mitochondrial Leader Sequence

From the Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907-1153

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.

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