OMA1-An integral membrane protease?

Abstract

OMA1 is a mitochondrial protease. Among its substrates are DELE1, a signaling peptide, which can elicit the integrated stress response, as well as the membrane-shaping dynamin-related GTPase OPA1, which can drive mitochondrial outer membrane permeabilization. OMA1 is dormant under physiological conditions but rapidly activated upon mitochondrial stress, such as loss of membrane potential or excessive reactive oxygen species. Accordingly, OMA1 was found to be activated in a number of disease conditions, including cancer and neurodegeneration. OMA1 has a predicted transmembrane domain and is believed to be tethered to the mitochondrial inner membrane. Yet, its structure has not been resolved and its context-dependent regulation remains obscure. Here, I review the literature with focus on OMA1's biochemistry. I provide a good homology model of OMA1's active site with a root-mean-square deviation of 0.9 Å and a DALI Z-score of 19.8. And I build a case for OMA1 actually being an integral membrane protease based on OMA1's role in the generation of small signaling peptides, its functional overlap with PARL, and OMA1's homology with ZMPSTE24. The refined understanding of this important enzyme can help with the design of tool compounds and development of chemical probes in the future.

Figure 1:

OMA1 shares substrates with PARL and the i-AAA protease. OMA1 can hydrolyze DELE1, OPA1, PGAM5 and PINK1, which leads to necroptosis, mitophagy, activation of the integrated stress response or apoptosis. OMA1 cleaves OPA1 at the S1 site, while the i-AAA protease cleaves OPA1 in close proximity at S2. Both proteases can digest each other in a context-dependent manner as well. PARL cleaves PGAM5 and PINK1, which both can be recognized by OMA1, too. PARL can hydrolyze OPA1 in yeast and flies but not in mammalian organisms.

Figure 2:

The AAA proteases are organized in a higher order complex. i-AAA faces the intramembrane space and can interact with SLP2 and PARL on the opposite site of the inner membrane (IM). m-AAA on the matrix side can interact with the prohibitins (PHB1 and PHB2) and presumably OMA1 on the intramembrane space-facing side of the IM. Genetic alterations of any of these members of the AAA protein complex impact OMA1 function.

Figure 3:

Homology model of OMA1’s active site based on ZMPSTE24 (PDB ID: 4AW6; shown greyed out.) The model is oriented with the amino-terminal end to the left (putative transmembrane domain III is depicted in blue) and the outset of the carboxyl end on the right (red). The catalytic zinc (pink) is coordinated by two histidines and a glutamate on transmembrane domains IV and V (green and yellow, respectively).

Figure 4:

The mature OMA1 protein has a number of α-helices (red) with evenly spaced hydrophobic amino acids with low solvent accessibility (dark squares), which could form a protein with overall six or seven transmembrane domains (indicated by roman numbers). The β-sheets (green) connecting transmembrane III and IV form part of the active site stabilized by a short α-helix. The zinc-binding histidines and glutamate on transmembrane domains IV and V are printed in bold.