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Integrative Structural and Computational Biology

Keren Lasker, PhD

Assistant Professor
Department of Integrative Structural and Computational Biology
California Campus
Laboratory Website
klasker@scripps.edu
(858) 784-8770

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

Our lab characterizes the structure, function, and adaptation of bacterial condensates. With this knowledge, we engineer synthetic condensates to manipulate the physiology and disease states of human cells.

Significance. Biomolecular condensates of protein and nucleoid acids have recently been recognized as an important organizing principle of cell biology across the tree of life. These dynamic assemblies compartmentalize and concentrate biomolecules involved in shared regulatory processes in cells, providing chemically distinct environments. Research over the past decade has greatly increased our understanding of the underlying biophysical principles and the regulation and roles of the condensate states in biological function and dysfunction. Further, aberrant condensate formation is associated with human diseases and neurodegeneration. Of
critical importance is then to determine how condensates orchestrate complex cellular behaviors and whether those can
be manipulated for therapeutic and synthetic applications.

Approach and innovation. We are establishing bacterial condensates, such as the PopZ condensate (Lasker et al, Nature Microbiology, 2020; Lasker et al, Nature Communications, 2022), as a model system to study emerging challenges in condensate biology. Studying these questions in bacterial systems is advantageous for the following reasons: (i) Bacterial model systems, such as E. coli and Caulobacter crescentus, are highly characterized and genetically amenable, providing a unique opportunity to establish a system-level understanding of condensate function. (ii) Bacteria thrive in a vast array of environments. As condensate assembly and properties are highly dependent on its cellular environment, examining condensates across related extremophiles provides a unique
opportunity to learn adaptation strategies. (iii) We can leverage our emerging understanding of bacterial condensates to establish new therapeutic strategies to treat bacterial infection. (iv) Bacterial condensates differ from those of human cells, providing opportunities for designer condensates to control biological processes. Below I provide a brief overview of two of our focus areas: bacterial condensates and condensate engineering.

Focus area 1. Dissecting the molecular grammar and cell biology of PopZ adaptation. PopZ is a hallmark protein for a-proteobacteria, a highly abundant class of bacteria closely linked to all complex life forms on Earth, including thermophilic and psychrophilic species. We leverage expertise in microbiology, phase separation biology, and computational modeling to develop PopZ from bacterial extremophiles as a model system for the study of condensate adaptation to temperature in vivo. We are charting two research directions that combined will: (i) provide a system-level understanding of the PopZ condensate in Caulobacter crescentus, (ii) define the molecular grammar and cell biology of PopZ temperature adaptation, (iii) elucidate the cytoplasm properties in psychrophilic and thermophilic bacteria that facilitate this condensation, and (iv) engineer temperature-dependent condensates. The results of these studies will contribute to our understanding of phase-separation biology and a framework for engineering bacteria for therapeutic and agricultural applications.

Focus area 2. PopTag as a system for clearing pathological aggregates. We recently demonstrated the utility of PopZ as a framework for engineering synthetic condensates (PopTag). Building on results from Focus area 1, we engineer PopTag to promote the clearance of protein aggregates associated with the development of disease.