The PARL family of mitochondrial rhomboid proteases - PubMed (original) (raw)

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The PARL family of mitochondrial rhomboid proteases

R Blake Hill et al. Semin Cell Dev Biol. 2010 Aug.

Abstract

Rhomboids are an ancient and conserved family of intramembrane-cleaving proteases, a small group of proteolytic enzymes capable of hydrolyzing a peptide bond within a transmembrane helix that anchors a substrate protein to the membrane. Mitochondrial rhomboids evolved in eukaryotes to coordinate a critical aspect of cell biology, the regulation of mitochondrial membranes dynamics. This function appears to have required the emergence of a structural feature that is unique among all other rhomboids: an additional transmembrane helix (TMH) positioned at the N-terminus of six TMHs that form the core proteolytic domain of all prokaryotic and eukaryotic rhomboids. This "1+6" structure, which is shared only among mitochondrial rhomboids, defines a subfamily of rhomboids with the prototypical family member being mammalian Parl. Here, we present the findings that in 11 years have elevated mitochondrial rhomboids as the gatekeepers of mitochondrial dynamics and apoptosis; further, we discuss the aspects of their biology that are bound to introduce new paradigm shifts in our understanding of how the organelle uses this unique type of protease to govern stress, signaling to the nucleus, and other key mitochondrial activities in health and disease.

Copyright 2009 Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Domain architecture of rhomboid proteases. Rhomboids are composed of a 6 TMH core domain found in prokaryotes with two subfamilies that differ in the placement of an additional TMH at either the N-terminus (“1+6” mitochondrial PARL subfamily) or the C-terminus (“6+1” RHO subfamily). High resolution structures of the 6 TMH core rhomboid domain from bacterial rhomboids have been determined [12-15,35] and show the architecture of the active site with the absolutely conserved Ser and His arranged in a manner akin to classical serine proteases. Based on this and other evidence, Ser is thought to act as a nucleophile and initiate catalysis on the polypeptide substrate. Histidine plays essential acid-base roles in catalysis. The figure was made using the software PyMOL [110] and 3B45.pdb [35].

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