The most severe from of malaria in human is caused by the pathogen Plasmodium falciparum (Pf). Clinical manifestation is strongly related to the sequestration of infected blood cells (iRBC), which is mediated by a variety of interactions between members of the clonally extremely variant var/Pf erythrocyte membrane family P1 (PfEMP1) family and host receptors. PfEMP1 ectodomains consist of Duffy-binding like (DBL) and cysteine-rich interdomain region (CIDR) adhesion domains. Despite a vast body of work the current knowledge of the mechanism underlying the PfEMP1 mediated host-pathogen interactions is substantially incomplete. The goal of the group is to obtain an in-depth understanding of the molecular machinery governing the process of PfEMP1-mediated cytoadhesion by the complementary use of molecular biology, biochemistry, x-ray crystallography and electron microscopy.

Research Projects

Towards a structural and functional model of the PfEMP1 mediated host-pathogen interactions

We have chosen a set of PfEMP1 proteins to represent the binding capabilities of the PfEMP1 family. Selected var genes as well as selected host receptors are cloned and expressed. The corresponding domain cassettes (DCs), full length PfEMP1 and receptor molecules are purified. The proteins are subjected to functional and structural studies to identify and map the binding capabilities of i) individual residues within a domain, ii) individual domains with DCs and iii) DCs within full-length proteins. Furthermore, interaction studies using fluorescently tagged DCs and full-length PfEMP1s as well as receptor molecules that are embedded in cell-like vesicles will be performed to enable imaging of host-pathogen interactions in a cell-like environment. Collectively, these results will provide a structural and functional model of PfEMP1 mediated interactions. Such model should allow establishing and predicting an atlas of interaction between pathogen and human host depending on the DCs content of the Pf strain and therefore opening strategies for patient specific treatment of malaria.

Publication Highlights

Laborgruppe Witt

Force spectroscopy of substrate molecules en route to the proteasome's active sites.
Classen M, Breuer S, Baumeister W, Guckenberger R, Witt S.
Biophys J. 2011 Jan 19;100(2):489-97. doi: 10.1016/j.bpj.2010.12.3689.

Laborgruppe Witt

The proteasome antechamber maintains substrates in an unfolded state.
Ruschak AM, Religa TL, Breuer S, Witt S, Kay LE.
Nature. 2010 Oct 14;467(7317):868-71. doi: 10.1038/nature09444.

All Publications


Neprilysin inhibits coagulation through proteolytic inactivation of fibrinogen
Burrell M, Ravnefjord A, Henderson SJ, Schweikart F, Fowler SB, Witt S, Hansson KM, Webster CI.
PLoS One. 2016 Jul 20;11(7):e0158114.doi: 10.1371/journal.pone.0158114.

Laborgrupp Witt

Monovalent IgG Molecules: Immunoglobulin Fc mutations that confer a stable monomeric structure
Wilkinson I, Fowler S, Burrell M, Corkill D, Witt S, Machiesky LA, Miller K, Hayes D, Morshed A, Borrok II M, Tsui P, Lowe D, Webster C.
MAbs. 2013 May-Jun;5(3):406-17. doi: 10.4161/mabs.23941.

Laborgruppe Witt

Force spectroscopy of substrate molecules ‘en route’ to the proteasome’s active sites.
Classen M, Breuer S, Baumeister W, Guckenberger R, Witt S.
Biophys J. 2011 Jan 19; 100(2): 489–497. doi: 10.1016/j.bpj.2010.12.3689

Laborgruppe Witt

The proteasome antechamber maintains substrates in an unfolded state.
Ruschak AM, Religa TL, Breuer S, Witt S, Kay LE.
Nature. 2010 Oct 14;467(7317):868-71. doi: 10.1038/nature09444.

Laborgruppe Witt

Structure and function of a novel type of ATP-dependent Clp protease.
Andersson FI, Tryggvesson A, Sharon M, Diemand AV, Classen M, Best C, Schmidt R, Schelin J, Stanne TM, Bukau B, Robinson CV, Witt S, Mogk A, Clarke AK.
J Biol Chem. 2009 May 15;284(20):13519-32. doi: 10.1074/jbc.M809588200. Epub 2009 Feb 23.

Laborgruppe Witt

Crystallization and preliminary X-ray analysis of the Thermoplasma acidophilum 20S proteasome in complex with protein substrates.
Felderer G, Groves M, Diez J, Pohl E, Witt S.
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Oct 1; 64(Pt 10): 899–902. Published online 2008 Sep 30. doi: 10.1107/S1744309108026791

Laborgruppe Witt

Mass Spectrometry Reveals the Missing Links in the Assembly Pathway of the Bacterial 20 S Proteasome.
Sharon M, Witt S, Glasmacher E, Baumeister W, Robinson CV.
J Biol Chem. 2007 Jun 22;282(25):18448-57. Epub 2007 Apr 12.

Laborgruppe Witt

Proteasome assembly triggers a switch required for active-site maturation.
Witt S, Kwon YD, Sharon M, Felderer K, Beuttler M, Robinson CV, Baumeister W, Jap BK.
Structure. 2006 Jul;14(7):1179-88.

Laborgruppe Witt

How to orient the functional GroEL-SR1 mutant for atomic force microscopy investigations.
Schiener J, Witt S, Hayer-Hartl M, Guckenberger R.
Biochem Biophys Res Commun. 2005 Mar 11;328(2):477-83.

Laborgruppe Witt

High-resolution imaging of single fluorescent molecules with the optical near-field of a metal tip.
Frey HG, Witt S, Felderer K, Guckenberger R.
Phys Rev Lett. 2004 Nov 12;93(20):200801. Epub 2004 Nov 10.

Stabilized Atomic Force Microscopy imaging in liquids using 2nd harmonic of cantilever motion for setpoint control.
Schiener J, Witt S, Stark M, Guckenberger R.
(2004) Review of Scientific Instruments, 75, 2564-2568.

Laborgruppe Witt

Distant downstream sequence determinants can control N-tail translocation during protein insertion into the endoplasmic reticulum membrane.
Nilsson I, Witt S, Kiefer H, Mingarro I, von Heijne G.
J Biol Chem. 2000 Mar 3;275(9):6207-13.

Conserved arginine-516 of Penicillium amagasakiense glucose oxidase is essential for the efficient binding of beta-D-glucose.
Witt S, Wohlfahrt G, Schomburg D, Hecht HJ, Kalisz HM.
Biochem J. 2000 Apr 15;347(Pt 2):553-9.

Laborgruppe Witt

1.8 and 1.9 A resolution structures of the Penicillium amagasakiense and Aspergillus niger glucose oxidases as a basis for modelling substrate complexes.
Wohlfahrt G, Witt S, Hendle J, Schomburg D, Kalisz HM, Hecht HJ.
Acta Crystallogr D Biol Crystallogr. 1999 May;55(Pt 5):969-77.

Laborgruppe Witt

Structural and kinetic properties of nonglycosylated recombinant Penicillium amagasakiense glucose oxidase expressed in Escherichia coli.
Witt S, Singh M, Kalisz HM.
Send to Appl Environ Microbiol. 1998 Apr;64(4):1405-11.


Dr. Susanne Witt

Phone: +49 40 42818-289
Fax: +49 40 42818-512
E-Mail: witt@bnitm.de


Frank Geisinger -422
Nikolas Mohr -422