The mitochondrial rhomboid protease: Its rise from obscurity to the pinnacle of disease-relevant genes

Chan, Eliana Y.L.; McQuibban, G. Angus

doi:10.1016/j.bbamem.2013.05.012

Cited by 38 publications

(25 citation statements)

References 117 publications

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“…Although rhomboid proteases are commonly believed to be constitutively active enzymes, 54 PARL has been suggested to be subject to direct post-translational control, 40 the PARK2 open reading frame downstream. C terminally-fluorescently-labeled PINK1, PINK1 R98W , PINK1 I111S , PINK1 G109L , TOMM20-PINK1 CTD , LETM1, LETM1 NTD -PINK1 CTD , mPARL S275A and hPARL S277A were generated by subcloning into monomeric variants of pmCherry-N1 and pEGFP-N1, respectively.…”

Section: Discussionmentioning

confidence: 99%

Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

et al. 2015

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Mutations in PINK1 and PARK2/Parkin are a main risk factor for familial Parkinson disease. While the physiological mechanism of their activation is unclear, these proteins have been shown in tissue culture cells to serve as a key trigger for autophagy of depolarized mitochondria. Here we show that ablation of the mitochondrial rhomboid protease PARL leads to retrograde translocation of an intermembrane space-bridging PINK1 import intermediate. Subsequently, it is rerouted to the outer membrane in order to recruit PARK2, which phenocopies mitophagy induction by uncoupling agents. Consistent with a role of this retrograde translocation mechanism in neurodegenerative disease, we show that pathogenic PINK1 mutants which are not cleaved by PARL affect PINK1 kinase activity and the ability to induce PARK2-mediated mitophagy. Altogether we suggest that PARL is an important intrinsic player in mitochondrial quality control, a system substantially impaired in Parkinson disease as indicated by reduced removal of damaged mitochondria in affected patients.

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Section: Discussionmentioning

confidence: 99%

Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

et al. 2015

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“…Moreover, some drugs including NSAIDs are also likely to cross membranes and affect rhomboid proteases in internal organelles in addition to the cell surface enzymes that we studied. One organelle that deserves particular attention is the mitochondria, in which a rhomboid protease is thought to switch substrates to trigger mitophagy and/or apoptosis upon damage (Chan and McQuibban, 2013). Interfering with this delicate substrate balance could prove particularly sensitive to membrane alterations, with implications for Parkinson’s disease.…”

Section: Discussionmentioning

confidence: 99%

A Subset of Membrane-Altering Agents and γ-Secretase Modulators Provoke Nonsubstrate Cleavage by Rhomboid Proteases

Urban

Moin

2014

Cell Reports

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SUMMARY Rhomboid proteases are integral membrane enzymes that regulate cell signaling, adhesion, and organelle homeostasis pathways, making substrate specificity a key feature of their function. Interestingly, we found that perturbing the membrane pharmacologically in living cells had little effect on substrate processing, but induced inappropriate cleavage of non-substrates by rhomboid proteases. A subclass of drugs known to modulate γ-secretase activity acted on the membrane directly and induced non-substrate cleavage by rhomboid proteases, but left true substrate cleavage sites unaltered. These observations highlight an active role for the membrane in guiding rhomboid selectivity, and caution that membrane-targeted drugs should be evaluated for cross-activity against membrane-resident enzymes that are otherwise unrelated to the intended drug target. Further, some γ-secretase-modulating activity or toxicity could partly result from global membrane effects.

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“…Proteolysis inside the cell membrane lies at the regulatory core of many pathways that are paramount to the health of a cell (Brown et al, 2000; Chan and McQuibban, 2013; De Strooper and Annaert, 2010; Wolfe, 2009). Each of the four known families of intramembrane proteases continue to be implicated in diverse pathologies including Alzheimer's disease, Parkinson's disease, cancer, malaria infection, hepatitis C virus maturation, tuberculosis virulence, and diabetes (Chan and McQuibban, 2013; De Strooper and Annaert, 2010; Manolaridis et al, 2013; Urban, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Each of the four known families of intramembrane proteases continue to be implicated in diverse pathologies including Alzheimer's disease, Parkinson's disease, cancer, malaria infection, hepatitis C virus maturation, tuberculosis virulence, and diabetes (Chan and McQuibban, 2013; De Strooper and Annaert, 2010; Manolaridis et al, 2013; Urban, 2009). In contrast to soluble proteases, which are arguably the best-understood enzymes and among the most effective therapeutic targets (Drag and Salvesen, 2010), the catalytic mechanisms of these membrane-immersed enzymes are incompletely understood and have proven difficult to target effectively for therapeutic benefit (Golde et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis

2016

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SUMMARY Intramembrane proteases signal by releasing proteins from the membrane, but despite their importance their enzymatic mechanisms remain obscure. We probed rhomboid proteases with reversible, mechanism-based inhibitors that allow precise kinetic analysis, and faithfully mimic the transition-state structurally. Contrary to expectation, inhibition by peptide aldehydes is non-competitive, revealing that, in the Michaelis complex, substrate does not contact the catalytic center. Structural analysis in a membrane revealed all extracellular loops of rhomboid make stabilizing interactions with substrate, but mainly through backbone interactions, explaining rhomboid's broad sequence selectivity. At the catalytic site, the tetrahedral intermediate lies covalently attached to the catalytic serine alone, with the oxyanion stabilized by unusual tripartite interactions with the sidechains of H150, N154, and the backbone of S201. We also unexpectedly visualized ‘extra’ substrate-enzyme interactions at the non-essential P2/P3 residues. These interactions foster potent rhomboid inhibition in living cells, thereby opening avenues for rational design of selective rhomboid inhibitors.

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The mitochondrial rhomboid protease: Its rise from obscurity to the pinnacle of disease-relevant genes

Cited by 38 publications

References 117 publications

Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy

A Subset of Membrane-Altering Agents and γ-Secretase Modulators Provoke Nonsubstrate Cleavage by Rhomboid Proteases

Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis

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