Team

Center for Molecular Signaling (PZMS)
Medical Biochemistry & Molecular Biology
Saarland University/Campus Homburg
66421 Homburg/Saar
Germany


 

Andrea Tirincsi  (PhD student)


Phone:
+49(0)6841-16-26515
Fax: +49(0)6841-16-26288
Email: s8antiri[at]stud.uni-saarland.de


“During my MSc, I studied Biochemistry at the National University of Ireland Galway and performed cancer research; examined the bone marrow microenvironment and its role in drug resistance in acute myeloid leukemia. Currently, I am doing my PhD at the Saarland University, Germany investigating a novel protein transport pathway beside the SRP and TRC pathways.”

 


 

Drazena Hadzibeganovic (PhD student)


Phone:
+49(0)6841-16-26515
Fax: +49(0)6841-16-26288
Email: drazenapervan[at]yahoo.com

“Using a variety of research methods, tools and techniques, our team aims to uncover the regulatory ATP-Ca2+ circuit of the ER in mammalian cells. The primary focus of my PhD project is to understand ATP-demand signals of the ER lumen and mechanisms of AXER activity.”

 


Mark Sicking (PhD student)


Phone:
+49(0)6841-16-26514
Fax: +49(0)6841-16-26288
Email: 
mark.sicking[at]uni-saarland.de

“Protein interactions and cellular malfunctions due to mutations are the focus of my PhD project. Effects of Sec61a mutations connected to a kidney disease are investigated by different techniques like live cell calcium imaging and in vitro protein transport. I also use different protein-protein interaction assays to identify additional components of the SND protein targeting pathway.”

 


 

Monika Lerner  (Technician)


Phone:
+49(0)6841-16-26323
Fax: +49(0)6841-16-26288
Email: 
Monika.Lerner[at]uks.eu

“I have been working in the Medical Biochemistry & Molecular Biology Department of the School of Medicine at the Saarland University for so many years now and I still enjoy my work very much, especially in this great team. Due to the many different methods and research approaches, my job is very varied and it never gets boring.”

 


Sven Lang, Dr. rer. nat. (Group leader)


Phone:
+49(0)6841-16-26510
Fax: +49(0)6841-16-26288
Email: sven.lang[at]uni-saarland.de

“Fascination & inspiration! Those are key terms I associate with science. Using scientific rigor to dissect biological questions and understand life at various scales is simply spellbinding. Thus, to me a PhD is the abbreviation for passion, hard work and dedication to scientific research.”

Research

 

 

Our protagonists


The endoplasmic reticulum (ER) is a single copy organelle of nucleated cells that spans as dynamic network from the nuclear envelope to the plasma membrane. As hub of the secretory pathway, the ER is essential for folding, modification, and quality control of many secretory and membrane proteins. In numbers, roughly one-third of newly synthesized proteins enter this organelle through a specialized protein translocon. Despite the energy-demanding nature of protein folding and quality control within the ER lumen neither autonomous ATP synthesis nor ADP phosphorylation occurs there. Instead, the ER relies on the import of ATP mediated by the ATP/ADP exchanger AXER. In addition, with its large volume and cell-wide distribution the ER represents the major intracellular reservoir for the important second messenger calcium. Thus, the ER is a nexus where protein, calcium, and energy homeostasis coalesce

 

Our mission


We focus on both transporters mentioned above, the Sec61-centric protein translocon and the ATP transporter AXER. From a broader perspective, we try to tackle one question. How are membrane transporters like AXER and Sec61 interwoven within the cellular fabric of signaling pathways and biochemical reactions? To better understand their cellular integration, we contemplate the dynamic recruitment of interaction partners regulating or expanding functionality of a transporter. Malfunctions of this process can perpetuate to cellular dysfunction and ultimately disease, as our own research shows. To address the question at hand, we use a broad mix of in vitro and live-cell imaging approaches that allow us to study the axial transport of proteins and ATP across the ER membrane as well as the dynamic interaction profile of the membrane transporters catalyzing those functions. By doing so, we hope to provide answers to the spatiotemporal assembly of the ER protein translocase as hub for protein homeostasis (s. Fig. 1) as well as the integration of AXER into the signaling network of cellular energy homeostasis (s. Fig. 2).

 

 

 

Our kung fu


In addition to the standardized molecular biology and biochemical routine work we employ

– Permanent and transient genetic manipulation of mammalian cells
– Live-cell imaging of intracellular Ca2+ and ATP distribution
– Synthetic and genetically encoded fluorescent probes
– Reconstituted and live-cell protein transport assays
– Bimolecular luminescent complementation
– Radioactive labelling of nascent proteins

Publications

2021

Pick T, Beck A, Gamayun I, Schwarz Y, Schirra C, Jung M, Krause E, Niemeyer BA, Zimmermannd R, Lang S, van Anken E, Cavalié A (2021) Remodelling of Ca2+ homeostasis is linked to enlarged endoplasmic reticulum in secretory cells. Cell Calcium 99, 102473; https://www.sciencedirect.com/science/article/pii/S0143416021001275

Sicking M, Jung M, Lang S (2021) Lights, Camera, Interaction: Studying Protein–Protein Interactions of the ER Protein Translocase in Living Cells. Int. J. Mol. Sci. 22, 10358; https://doi.org/10.3390/ijms221910358 

Sicking M, Lang S, Bochen F, Roos A, Drenth JPH, Zakaria M, Zimmermann R, Linxweiler M (2021) Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex. Cells 10, 1036

 

2020

Klein MC, Lerner M, Nguyen D, Pfeffer S, Dudek J, Förster F, Helms V, Lang S, Zimmermann R (2020) TRAM1 protein may support ER protein import by modulating the phospholipid bilayer near the lateral gate of the Sec61 channel, Channels 14, 28-44

Kriegler T, Lang S, Notari L & Hessa T (2020) Prion Protein Translocation Mechanism Revealed by Pulling Force Studies. Jmb. 20: 30373-9, https://doi.org/10.1016/j.jmb.2020.05.022

Kriegler T, Lang S, Notari L, Hessa T. (2020) Supporting data on Prion Protein Translocation Mechanism Revealed by Pulling Force Studies. Data in Brief 31: 105931

Van Nieuwenhove E, Barber JS, Neumann J, Smeets E, Willemsen M, Pasciuto E, Prezzemolo T, Lagou V, Seldeslachts L, Malengier-Devlies B, Metzemaekers M, Haßdenteufel S, Kerstens A, van der Kant R, Rousseau F, Schymkowitz J, Di Marino D, Lang S, Zimmermann R, Schlenner S, Munck S, Proost P, Matthys P, Devalck C, Boeckx N, Claessens F, Wouters C, Humblet-Baron S, Meyts I, Liston A. (2020) Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia. Journal of Allergy and Clinical Immunology, doi:10.1016/ j.jaci.2020.03.034

Schorr S, Nguyen D, Haßdenteufel S, Nagaraj N, Cavalié A, Greiner M, Weissgerber P, Loi M, Paton AW, Paton JC, Molinari M, Förster F, Dudek J, Lang S, Helms V, Zimmermann R. (2020) Proteomics identifies signal peptide features determining the substrate specificity in human Sec62/Sec63-dependent ER protein import. FEBS Journal, doi:10.1111/febs.15274

Zimmermann R, Lang S. (2020) A Little AXER ABC: ATP, BiP, and Calcium Form a Triumvirate Orchestrating Energy Homeostasis of the Endoplasmic Reticulum. Contact 3: 1-12


2019

Lang S, Hilsabeck TA, Wilson KA, Sharma A, Bose N, Brackman DJ, Beck JN, Chen L, Watson MA, Killilea DW, Ho S, Kahn A, Giacomini K, Stoller ML, Chi T, Kapahi P. (2019) A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster. PLOS Genetics 15, e1008318

Haßdenteufel S, Nguyen D, Helms V, Lang S, Zimmermann R. (2019) ER import of small human presecretory proteins: components and mechanisms. FEBS Letters 593: 2506-2524

Lang S, Nguyen D, Pfeffer S, Förster F, Helms V, Zimmermann R. Functions and mechanisms of the human ribosome-translocon complex. In Macromolecular Protein Complexes II: Structure and Function pp. 83-141, ISBN 978-3-030-28150-2


2018

Nguyen D, Stutz R, Schorr S, Lang S, Pfeffer S, Freeze HH, Förster F, Helms V, Dudek J, Zimmermann R. Proteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import. (2018) Nature Communications (2018) 9: 3765

Klein M-C, Zimmermann K, Schorr S, Landini M, Klemens PAW, Altensell J, Jung M, Krause E, Nguyen D, Helms V, Rettig J, Fecher-Trost C, Cavalié A, Hoth M, Bogeski I, Neuhaus HE, Zimmermann R, Lang S, Haferkamp I. (2018) AXER is an ATP/ADP exchanger in the membrane of the endoplasmic reticulum. Nature Communications 9: 3489


2017

Haßdenteufel S, Sicking M, Schorr S, Aviram N, Fecher-Trost C, Schuldiner M, Jung M, Zimmermann R, Lang S. hSnd2 protein represents an alternative targeting factor to the endoplasmic reticulum in human cells. FEBS Letters (2017) 591: 3211-3224

Lang S, Pfeffer S, Lee P-H, Cavalié A, Helms V, Förster F, Zimmermann R. (2017) An Update on Sec61 Channel Functions, Mechanisms, and Related Diseases. Frontiers in Physiology 8: 887


2015

Chi T, Kim M, Lang S, Bose N, Kahn A, Flechner L, Blaschko S, Zee T, Muteliefu G, Bond N, Kolipinski M, Fakra S, Mandel N, Miller J, Ramanathan A, Killilea D, Brückner K, Kapahi P, Stoller M. (2015) A Drosophila Model Identifies a Critical Role for Zinc in Mineralization for Kidney Stone Disease. PLOS ONE 10: e0124150


2014 & before

Harz C, Ludwig N, Lang S, Werner T, Galata V, Backes C, Schmitt K, Nickels R, Krause E, Jung M, Rettig J, Keller A, Menger M, Zimmermann R, Meese E. Secretion and immunogenicity of the meningioma-associated antigen TXNDC16. (2014) Journal of Immunology 193: 3146-3154

Pfeffer S, Dudek J, Gogala M, Schorr S, Linxweiler J, Lang S, Becker T, Beckmann R, Zimmermann R, Förster F. Structure of the mammalian oligosaccharyl-transferase complex in the native ER protein translocon. (2014) Nature Communications 5: 3072

Pfeiffer N, Dirndorfer D, Lang S, Miesbauer M, Zimmermann R, Winklhofer K, Tatzelt J. (2013) Structural features within the nascent chain regulate alternative targeting of secretory proteins to mitochondria. EMBO Journal 32: 1036-1051

Pfeffer S, Brandt F, Hrabe T, Lang S, Eibauer M, Zimmermann R, Förster F. (2012) Structure and 3D Arrangement of Endoplasmic Reticulum Membrane-Associated Ribosomes. Structure 20: 1508-1518

Dudek J, Lang S, Schorr S, Linxweiler J, Greiner M, Zimmermann R. (2013) Analysis of protein translocation into the endoplasmic reticulum of human cells. In Membrane Biogenesis: Methods and Protocols pp. 285-299, ISBN 978-1-62703-486-9

Johnson N, Vilardi F, Lang S, Leznicki P, Zimmermann R, High S. (2012) TRC40 can deliver short secretory proteins to the Sec61 translocon. Journal of Cell Science 125: 3612-3620

Schäuble N*, Lang S*, Jung M, Cappel S, Schorr S, Ulucan Ö, Linxweiler J, Dudek J, Blum R, Helms V, Paton J, Paton A, Cavalié A, Zimmermann R. ((2012) BiP-mediated closing of the Sec61 channel limits Ca2+ leakage from the ER. EMBO Journal 31: 3282-3296 (*NS and SL contributed equally to this work)

Lang S, Benedix J, Fedeles S, Schorr S, Schirra C, Schäuble N, Jalal C, Greiner M, Haßdenteufel S, Tatzelt J, Kreutzer B, Edelmann L, Krause E, Rettig J, Somlo S, Zimmermann R, Dudek J. (2012) Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides into the endoplasmic reticulum of mammalian cells. Journal of Cell Science 125: 1958-1969

Lang S, Schäuble N, Cavalié A, Zimmermann R. (2011)  Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca(2+) Leak Channels in the ER Membrane and their Regulatory Mechanisms. Journal of Visualized Experiments: e2730

Lang S, Erdmann F, Jung M, Wagner R, Cavalié A, Zimmermann R. (2011)  Sec61 complexes form ubiquitous ER Ca(2+) leak channels. Channels 5: 228-235

Erdmann F, Schäuble N, Lang S, Jung M, Honigmann A, Ahmad M, Dudek J, Benedix J, Harsman A, Kopp A, Helms V, Cavalié A, Wagner R, Zimmermann R. (2011) Interaction of calmodulin with Sec61alpha limits Ca2+ leakage from the endoplasmic reticulum. EMBO Journal 30: 17-31 (recommendation by F1000Prime)

Greiner M, Kreutzer B, Lang S, Jung V, Cavalié A, Unteregger G, Zimmermann R, Wullich B. (2011) Sec62 protein level is crucial for the ER stress tolerance of prostate cancer. The Prostate 71: 1074-1083

Erdmann F, Jung M, Eyrisch S, Lang S, Helms V, Wagner R, Zimmermann R. (2009) Lanthanum ions inhibit the mammalian Sec61 complex in its channel dynamics and protein transport activity. FEBS Letters 583: 2359-2364

News

23.09.2021:
Again congrats to Mark, this time for his contribution to the studies on protein–protein interactions of the ER protein translocase in living cells (published recently in the International Journal of Molecular Sciences).

27.04.2021:
Congrats to Mark for publishing his review article on Sec61-channelopathies.

19.04.2021:
We are happy that Gamar decided to join the lab as master student.

​17.11.2020:
Our new rotational master student Gamar started in the lab today.
Welcome, Gamar!

30.10.2020:
Drazena’s grant proposal “AXERcise 1” received a positive evaluation and will be funded. Thank you, SFB894!