Organization of cytoplasm across space and time
Previous and Current Research
Many key biochemical reactions take place in the cytoplasmic environment. However, we still know very little about the organization of the cytoplasm and the role of specialized cytoplasmic compartments such as RNP granules in regulating cellular functions. My research group aims to elucidate molecular principles underlying the spatiotemporal organization of the cytoplasm. We are particularly interested in understanding how the cytoplasm changes upon environmental perturbations and stress (Figure 1). Stressed cells undergo controlled changes on many levels to alter their physiology and metabolism. Many of these changes may directly result from alterations in the structure and organization of the cytoplasm. Understanding these structural changes and how they promote organismal survival is our key aim.
To investigate this question, we use cell biological, biochemical, biophysical and genetic approaches and diverse model systems, such as yeast, Dictyostelium, and cultured mammalian cells, thus allowing us to cover a wide range of different organismal life styles. Our findings so far indicate that the mechanisms by which macromolecules assemble into compartments are diverse and involve dedicated cellular factors, such as prion-like proteins that promote the formation of liquid compartments, or protein self-assembly pathways that are controlled by changes in global parameters such as the cytosolic pH.
Importantly, the ability to form such compartments comes with a cost, as many compartment-forming proteins have a high propensity to misfold and aggregate. Indeed, we could recently show that compartment-forming proteins have very unusual molecular properties and are associated with age-related diseases (Patel et al., 2015). Thus, our long-term aim is to gain insight into the important link between the compartment-forming abilities of proteins and age-related protein misfolding diseases.
Future Projects and Goals
- Identify protein factors, domains, and sequence motifs that are required for the formation of macromolecular assemblies
- Analyze the molecular mechanisms underlying the formation of macromolecular assemblies, with a focus on the protein quality control machinery, post-translational modifications, and the cytoskeleton
- Proteome-wide genetic and chemical screens to identify modifiers of macromolecular assembly
- Investigate how the ability to form macromolecular assemblies affects the physiological state of a cell, determines developmental decisions, and contributes to diseases and aging
Methodological and Technical Expertise
- Genetics and cell biology of S. cerevisiae, Dictyostelium, and cultured mammalian cells
- Fluorescence microscopy and time-lapse imaging
- Biophysical approaches such FRAP and photoconversion to study intracellular dynamics
- Biochemical reconstitution assays and in vitro and in vivo aggregation assays
Avinash Patel, Hyun-Ok Kate Lee, Louise Jawerth, Shovamayee Maharana, Marcus Jahnel, Marco Y Hein, Stoyno Stoynov, J. Mahamid, Shambaditya Saha, Titus Franzmann, Andrei Pozniakovski, Ina Poser, Nicola Maghelli, Loic Royer, Martin Weigert, Eugene W Myers, Stephan W. Grill, David N. Drechsel, Anthony Hyman, Simon Alberti
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.
Cell, 162, pp. 1066–1077. (2015)
Sonja Kroschwald, Shovamayee Maharana, Daniel Mateju, Liliana Malinovska, Elisabeth Nüske, Ina Poser, Doris Richter, Simon Alberti
Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules.
Elife, 4, e06807. (2015)
Liliana Malinovska, Sandra Palm, Kimberley Gibson, Jean-Marc Verbavatz, Simon Alberti
Dictyostelium discoideum has a highly Q/N-rich proteome and shows an unusual resilience to protein aggregation.
Proc Natl Acad Sci USA, 112, pp. 2620–2629 (2015)
Ivana Petrovska, Elisabeth Nüske, Matthias Munder, Gayathrie Kulasegaran, Liliana Malinovska, Sonja Kroschwald, Doris Richter, Karim Fahmy, Kimberley Gibson, Jean-Marc Verbavatz, Simon Alberti
Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation.
Elife, 3, e02409. (2014)
Alberti S, Halfmann R, King O, Kapila A, Lindquist S
A systematic survey identifies prions and illuminates sequence features of prionogenic proteins.
Cell, 137, pp. 146–158. (2009)