Get to know: Liudmila Andreeva
Liudmila Andreeva is a structural biologist and biochemist with a focus on innate immunity, inflammation and cancer. Specifically, she has investigated the major cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), which initiates type I interferon response upon DNA binding. Using X-ray crystallography together with biophysical and biochemical assays, she demonstrated that cGAS cooperatively binds long activator DNA species forming oligomers or “DNA-protein ladders”, which serve as a molecular “ruler” to specifically distinguish between short harmless and long “pathogenic” DNA species [1]. This discovery fired up Liudmila’s interest in studying structures and dynamics of higher-ordered supramolecular assemblies in immunity and inflammation, and guided her to the elucidation of other oligomers in innate immunity – inflammasomes. Inflammasomes are supramolecular machineries that trigger secretion of pro-inflammatory peptides (cytokines) and cell death, thus initiating inflammation.
Mechanistically, danger signals in our bodies trigger oligomerization of inflammasome sensor proteins, which initiates a downstream oligomerization cascade resulting in a formation of the active inflammasome complex, which at the end can be seen as a stack of various oligomers. These active inflammasomes can now activate a type of molecular scissor that trims other dormant proteins into their active forms. These in turn can punch holes in the cell membrane causing the cell to burst and release its components inducing inflammation. The human body has 26 sensor proteins, which can lead to inflammasome formation. All of them have their unique specificity to danger signals but converge on the downstream machinery.
Remarkably, despite the fact that the majority of these sensors are built very similarly on a domain level, every inflammasome seems to use a different approach to form an active oligomeric platform for downstream signaling. While some inflammasomes sensors form active oligomers directly from monomeric proteins, others “get together” as a phase separation droplet or switch from one “inactive” oligomeric form into another “active” oligomeric form [2].
Liudmila Andreeva uses cryo-electron microscopy, as well as various biochemical and cell-based methods to study the mechanics and acrobatics of various inflammasome sensors, which have been linked to such pathologies as autoimmunity, neurodegeneration, cancer and many others. Interested candidates for scientific positions may send their CV to Liudmila.Andreeva@med.uni-tuebingen.de. We will stay posted and hope that Liudmila Andreeva and her group continue to enjoy their research within iFIT!
[1] Andreeva L, Hiller B, Kostrewa D, Lässig C, de Oliveira Mann CC, Jan Drexler D, Maiser A, Gaidt M, Leonhardt H, Hornung V, Hopfner KP. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature. 2017 Sep 21;549(7672):394-398. doi: 10.1038/nature23890. Epub 2017 Sep 13. PMID: 28902841.
[2] Andreeva L, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, Wu H. NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell. 2021 Dec 22;184(26):6299-6312.e22. doi: 10.1016/j.cell.2021.11.011. Epub 2021 Dec 2. PMID: 34861190; PMCID: PMC8763037.