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Molecular Cell Biophysics
The Cosentino group aims to understand the molecular mechanisms of membrane pore formation by pore forming proteins (PFPs), a big class of proteins with crucial functions in infection, immunity, cancer and neurodegeneration. Specifically, we focus on PFPs involved in apoptosis and pyroptosis, two therapeutically relevant regulated cell death processes. To dissect the spatio-temporal assembly of membrane pores we apply several biophysical approaches, including quantitative single molecule imaging.
Research topics
- Spatio-temporal assembly of Gasdermins pores in pyroptosis
- Modulation of Gasdermin pore formation by the membrane environment
- Crosstalk between apoptosis and pyroptosis
- Modulation of cell death outcome
Model systems
- Protein reconstitution in artificial membrane systems (i.e. liposomes, supported lipid bilayers, nanodiscs)
- Mammalian cells endogenously or transiently expressing PFPs
- Isolated organelles and supported plasma membranes
Methods
- Expression and purification of fluorescently-labeled PFPs
- Activity and permeability assays of PFPs and cofactors
- Chemical or optogenetic activation of regulated cell death
- Single molecule fluorescence imaging and super resolution microscopy
- Stoichiometric analysis of protein complexes
- Atomic force microscopy and spectroscopy
Selected publications
Margheritis E, Kappelhoff S, Danial J, Gehle N, Kohl W, Kurre R, Gonzalez-Montoro A & Cosentino K (2024) Gasdermin D cysteine residues synergistically control its palmitoylation-mediated membrane targeting and assembly. The EMBO Journal 0:1-24. pdf
Kappelhoff S, Margheritis EG & Cosentino K (2024) New insights into GSDMD pore formation. Biochemical Society Transactions 52:681-92. pdf
Cosentino K, Hertlein V, Jenner A, Dellmann T, Gojkovic M, Peña-Blanco A, Dadsena S, Wajngarten N, Danial JSH, Thevathasan JV, Mund M, Ries J, & Garcia-Saez AJ (2022) The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation. Molecular Cell 82: 933-949. pdf