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Principal Investigator

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P19  Lars Schäfer
Group Leader

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Professor for Theoretical Chemistry since 2014,
Ruhr-University Bochum

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Former member of the 
Institute of Physical and
Theoretical Chemistry
Goethe University Frankfurt a.M.


P19 Structural organization of macromolecular complexes in membranes: The MHC class I peptide-loading complex


Assemblies of membrane proteins play central roles in many cellular processes, yet often little is known about their higher-order structural organization. The goal of this project is to characterize the molecular architecture and interactions of the MHC class I peptide-loading complex (PLC), a membrane-bound supercomplex that is involved in the mammalian antiviral immune response, the rejection of organ transplants, and cancer. In particular, we aim at elucidating the structures of the N-terminal TMD0 domains of the heterodimeric ABC transporter TAP, 4-TM bundles that are key interaction hubs in the PLC, and study their interactions with core TAP complex and the chaperone tapasin.

Furthermore, we will investigate how the other components of the supercomplex arrange themselves around this platform. The ultimate aim is to obtain a detailed picture of the atomistic structure, interactions, and dynamics of the entire PLC. To reach these goals, we will adopt an integrative computational modeling approach that extracts the maximum information concealed in the available host of experimental and evolution data, in close collaboration with other groups in the collaborative research center. The long-term goal is to characterize other, even larger macromolecular assemblies in cell membranes.

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Publications

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Fisette O, Wingbermühle S, Tampé R, Schäfer LV (2015) Molecular mechanism of peptide editing in the Tapasin-MHC I complex. Sci Rep 5, 19085.

Blees A, Reichel K, Trowitzsch S, Fisette O, Bock C, Abele R, Hummer G, Schäfer LV, Tampé R (2015) Assembly of the MHC I peptide-loading complex determined by a conserved ionic lock-switch. Sci Rep 5, 17341.

Fleischmann G, Fisette O, Thomas C, Wieneke R, Tumulka F, Schneeweiss C, Springer S, Schäfer LV, Tampé R (2015) Mechanistic basis for epitope proofreading in the peptide loading complex. J Immunol 195, 4503-13.

Gopal SM, Kuhn AB, Schäfer LV (2015) Systematic evaluation of bundled SPC water for biomolecular simulations. Phys Chem Chem Phys 17, 8393-8406.

Eggensperger S, Fisette O, Parcej D, Schäfer LV, Tampé R (2014) An annular lipid belt is essential for allosteric coupling and viral inhibition of the antigen translocation complex TAP. J Biol Chem 289, 33098-108.

Lloris-Garcera P, Slusky JSG, Seppälä S, Prieß M, Schäfer LV, von Heijne G (2013) In vivo Trp scanning of the small multidrug resistance protein EmrE confirms 3D structure models. J Mol Biol 425, 4642-51.

Majsnerowska M, Hänelt I, Wunnicke D, Schäfer LV, Steinhoff H-J, Slotboom DJ (2013) Substrate-induced conformational changes in the S-component ThiT from an Energy Coupling Factor transporter. Structure 21, 861-867.

Wassenaar TA, Ingolfsson HI, Prieß M, Marrink SJ, Schäfer LV (2013) Mixing Martini: Electrostatic Coupling in Hybrid Atomistic/Coarse-grained Biomolecular Simulations. J Phys Chem B 117, 3516-3530.

de Jong DH, Singh G, Bennett WFD, Arnarez C, Wassenaar TA, Schäfer LV, Periole X, Tieleman DP, Marrink SJ (2013) Improved parameters for the Martini coarse-grained protein force field. J Chem Theory Comput 9, 687-697.

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Collaborations

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Tampé (P16), Dötsch/Bernhard (P2), Prisner (P7), Kühlbrandt (P1), Abele (P9)