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Mitochondrial Precursor Proteins

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Most precursors are targeted to the mitochondria by a cleavable N-terminal amphipathic signal sequence called the presequence. Precursors targeted to the mitochondrial membranes or intermembrane space contain additional non-cleavable internal import signals.

Cytosolic chaperone and co-chaperone complexes use energy from ATP hydrolysis to bind and stabilize the unfolded precursors. This keeps them in a disaggregated state before the complexes can transport them to the translocons on the mitochondrial membranes.

Import receptors on the mitochondrial membrane can recognize both presequences and import signals to allow the unfolded peptides to thread through the TOM-TIM complexes.

Proteins targeted to the mitochondrial membranes contain internal hydrophobic stop-transfer signal sequences that arrest their translocation. Once the presequence is cleaved by mitochondrial processing peptidases these proteins are pulled into the intermembrane space and directly inserted into the inner membrane, using the hydrophobic sequence as an anchor.

For proteins targeted to the intermembrane space, inner membrane proteases cleave the presequence as the chaperones help the processed precursors fold into their native conformation.

Proteins containing matrix-targeting sequences are cleaved by matrix proteases and the processed peptide is folded and released as a functional protein.

Overview

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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70 chaperones are targetted to TOM20-TOM22 receptor complexes.

Most of the mitochondrial precursors recognized by TOM20 carry cleavable alpha-helical amphipathic presequences, whereas precursors recognized by TOM70 receptors have non-cleavable internal import signals. Similar to the presequences of mitochondrial precursors, ER precursors also carry alpha-helical signal sequences. TOM20 recognizes the mitochondrial precursor by interacting with three leucine residues, characteristic of a mitochondrial presequence. In addition, a shallow binding groove of TOM20 allows it to accommodate only amphipathic alpha-helices while avoiding the hydrophobic alpha-helices of ER precursors.

Presequences have no consensus motif; however, the nature of the amino acid residues determines the fidelity of the recognition process. Presequences such as the matrix targetting sequences have hydrophobic residues on one side of the helix and hydrophilic residues lining the other. During translocation, these hydrophobic residues interact with non-polar acyl chains of the bilayer core. In contrast, the hydrophilic residues on the other side of the presequence participate in electrostatic interactions with the polar phosphate heads of the lipid bilayer. Additionally, the hydrophilic positively charged residues on the presequences also enhance the precursor’s affinity towards negative charges on the matrix side of the inner membrane, thereby providing it the necessary energy required to cross the lipid bilayer and initiate the translocation process.

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Mitochondrial Precursor Proteins

Cytosolic Chaperones

Heat Shock Proteins 70

Mitochondrial Import Stimulation Factors

TOM70 TOM37 Receptors

TOM20 TOM22 Receptor Complexes

Cleavable Alpha Helical Presequences

Non Cleavable Internal Import Signals

Amphipathic Alpha Helices

Lipid Bilayer Interactions