Prof. Marius Lemberg

University of Cologne

Project P1: Substrate Recognition and Cleavage by the Mitochondrial Rhomboid Protease PARL


Rhomboids are universally conserved intramembrane serine proteases that impact on a variety of important cellular processes.
While analysis of bacterial rhomboids has provided first insights of how cognate transmembrane domains are selected for cleavage, for the more distant mitochondrial rhomboid protease PARL still only very little is known.


Central aim of this project within the FOR2290 is to decipher how PARL selects its substrates. This is of particular relevance since PARL has an active site topology opposite to classical rhomboid proteases in bacteria and the eukaryotic secretory pathway, indicating that it has evolved a unique substrate selection mechanism.

Publications (FOR 2290)


Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state.

Siebert V, Silber M, Heuten E, Muhle-Goll CLemberg MK.

J Biol Chem. 2022 Jul 31:102321. doi: 10.1016/j.jbc.2022.102321. Online ahead of print.PMID: 35921890 Free article.

Lysyk L, Brassard R, Arutyunova E, Siebert V, Jiang Z, Takyi E, Morrison M, Young HS, Lemberg MK, O'Donoghue AJ, Lemieux MJ.

J Biol Chem. 2021 Feb 5:100383. doi: 10.1016/j.jbc.2021.100383. Online ahead of print. PMID: 33556373 Free article.


Signal Peptide Peptidase-Type Proteases: Versatile Regulators with Functions Ranging from Limited Proteolysis to Protein Degradation.

Yücel SS, Lemberg MK.

J Mol Biol. 2020 Aug 21;432(18):5063-5078. doi: 10.1016/j.jmb.2020.05.014. Epub 2020 May 26. PMID: 32464132 Review.

The Metastable XBP1u Transmembrane Domain Defines Determinants for Intramembrane Proteolysis by Signal Peptide Peptidase.

Yücel SS, Stelzer W, Lorenzoni A, Wozny M, Langosch D, Lemberg MK.

Cell Rep. 2019 Mar 12;26(11):3087-3099.e11. doi: 10.1016/j.celrep.2019.02.057. PMID:30865896


 Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments.

Lichtenthaler SF, Lemberg MK, Fluhrer R.

EMBO J. 2018 Aug 1;37(15). pii: e99456. doi: 10.15252/embj.201899456. Epub 2018 Jul 5. Review.


Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes.

Kronenberg-Versteeg D, Eichmann M, Russell MA, de Ru A, Hehn B, Yusuf N, van Veelen PA, Richardson SJ, Morgan NG, Lemberg MK, Peakman M.


"Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics."
Langosch, D., Scharnagl, C.,  Steiner, H., Lemberg, M.K. (2015)

Trends Biochem Sci. 2015 Jun;40(6):318-27


Publications FOR 2290 PI's

Research Unit FOR 2290