DNA molecules tell nanoparticles how to self-assemble

Nature uses self-assembly to make a diversity of complex structures, such as biomolecules, virus shells, and cytoskeletal filaments. Today a key challenge is to translate this assembly process to artificial systems. DNA-coated nanoparticles provide a particularly promising approach to realizing this vision, since the base sequences can be designed to encode the formation of a chosen structure.

A recent publication from the Rogers Lab shows that interactions between DNA-coated particles can be encoded using DNA oligomers dispersed in solution that bind the particles together.  By changing the linker sequences in solution, Ph.D. students Janna Lowensohn and Alex Hensley showed that the same set of components can be directed to form a variety of different crystal structures. Going forward, this approach may be used to create programmable materials that can sense and respond to their environment.


DNA instructions

Paper: Self-Assembly and Crystallization of DNA-Coated Colloids via Linker-Encoded Interactions. Lowensohn J, Hensley A, Perlow-Zelman M, Rogers WB. Langmuir. 2020 Feb 18. doi: 10.1021/acs.langmuir.9b03391. (PubMed abstract)

Autism-linked Gene Keeps Brains in Balance

Mutations in the human Shank3 gene – so called “Shankopathies” – are strongly associated with Autism-spectrum disorders and intellectual disability, and appear to increase risk for a number of other disorders such as bipolar disorder and epilepsy. How it is that loss of function of this single gene generates pervasive disfunction within the neural circuits that underlie cognition and behavior is not understood. Now a recent report from the Turrigiano lab at Brandeis (Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1. Neuron. 2020 Mar 10. ) sheds light into this process, by showing how Shank3 loss disables mechanisms that normally act to keep brain circuitry in balance. Much as your body maintains a constant temperature through the use of internal thermostats and negative feedback mechanisms, brain circuits maintain balanced activity – neither too low and unresponsive, nor too high and hyperactive – by using a set of so-called “homeostatic” plasticity mechanisms to keep circuit excitability within an ideal range. This process is especially important during childhood and adolescence, because developing circuits can easily get out of balance as brain circuitry changes as a result of normal developmental processes.

Using mouse and rat models of human Shankopathies, the team, led by Research Associate Vedakumar Tatavarty, found that loss of Shank3 disables these homeostatic plasticity mechanisms and prevents brain circuits from compensating for changes to sensory drive. These defects in homeostatic plasticity are due to acute loss of Shank3 within individual neurons, meaning they are not an indirect effect of messed-up circuit wiring caused by loss of the gene throughout development. This finding suggests that Shank3 is a fundamental part of the cellular machinery that normally mediates homeostatic plasticity. The team went on to show that homeostatic plasticity could be restored after Shank3 loss by treatment with Lithium – a drug with a long history of use to treat neuropsychiatric disorders such as bipolar disorder – and that Lithium was also able to reduce a repetitive grooming behavior in mice that lack Shank3. These mice normally groom to excess, even to the point of self-injury, but a week of lithium treatment was able to reduce grooming to normal levels.

So do these findings suggest that Lithium might be useful in treating human Shankopathies? While Lithium remains the frontline treatment for some human disorders such as bipolar disorder, it is not well-tolerated, says Turrigiano, “and of course we cannot extrapolate from findings in mice directly to humans. Instead, we hope to use Lithium as a tool to reveal the pathways that can restore homeostatic plasticity in Shankopathies, which in the long term may allow us to design better, more specific interventions”. Defects in homeostatic plasticity have been implicated in a wide range of human brain disorders ranging from Autism spectrum disorders to Alzheimer’s disease, so these studies are likely to have important implications for overall brain health.

Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1. Tatavarty V, Torrado Pacheco A, Groves Kuhnle C, Lin H, Koundinya P, Miska NJ, Hengen KB, Wagner FF, Van Hooser SD, Turrigiano GG. Neuron. 2020 Mar 10. pii: S0896-6273(20)30184-7. doi: 10.1016/j.neuron.2020.02.033.

Gelation without Attraction

By Bulbul Chakraborty

Gels are one of the most puzzling of all solids. Originally coined as a short form of gelatin, gels can be jelly-like as in Jello, or quite hard as in silica gels. They appear in suspensions of particles at extremely low volume fractions, and yet they are rigid. The conventional wisdom is that gels are a consequence of arrested phase separation of the suspended particles from the fluid. A natural mechanism for the arrest is attraction between the particles, which leads to the formation of filamentous networks of particles weaving through the suspending fluid.

Attraction has been viewed as being essential to the formation of gels. However, a new study published in Physical Review Research led by Carl Merrigan from the Chakraborty group, shows that “active particles” can gel even in the absence of physical attraction. Active matter, composed of particles that convert ambient energy to directed motion, has emerged as an important model for the collective behavior of biological matter such as bacterial suspensions. Using a combination of theoretical analysis and numerical simulations, the collaboration between the groups of Chakraborty and Shokef (Tel Aviv University) showed that the directed motion acts like an effective attraction, leading to gelation of the active particles.

The figure below shows the structure of these gels. As the particles become more active, they jam into clusters of immobile particles (red) surrounded by fluid regions (blue), and often opening up voids. Intriguingly, these active particles, which repel each other also show a transition from a dense glassy solid to a gel as the speed of directed motion is increased. The remarkable similarity between the behavior of passive particles with attraction and active particles suggests that biological entities could form solid-like aggregates without any physical or chemical attraction, purely as a consequence of their dynamics.

Reasearch image from Gelation without Attraction post

Goode, Gelles and Kondev labs synergize in discovery of a new synergistic actin depolymerization mechanism

Shashank Shekhar, Jane Kondev, Jeff Gelles and Bruce Goode

Shashank Shekhar, Jane Kondev, Jeff Gelles and Bruce Goode

All animal and plant cells contain a highly elaborate system of filamentous protein polymers called the actin cytoskeleton, a scaffold that can be rapidly transformed to alter a cell’s shape and function. A critical step in reconfiguring this scaffold is the rapid disassembly (or turnover) of the actin filaments. But how is this achieved? It has long been known that the protein Cofilin plays a central role in this process, but it has been unclear how Cofilin achieves this feat. Cofilin can sever actin filaments into smaller fragments to promote their disassembly, but whether it also catalyzes subunit dissociation from filament ends has remained uncertain and controversial. Until now, this problem has been difficult to address because of limitations in directly observing Cofilin’s biochemical effects at filament ends. However, a new study published in Nature Communications led by postdoctoral associate Dr. Shashank Shekhar, jointly mentored by Bruce Goode, Jeff Gelles and Jane Kondev, uses microfluidics-assisted single molecule TIRF imaging to tackle the problem.

The new study shows that Cofilin and one other protein (Srv2/CAP) intimately collaborate at one end of the actin filament to accelerate subunit dissociation by over 300-fold! These are the fastest rates of actin depolymerization ever observed. Further, these results establish a new paradigm in which a protein that decorates filament sides (Cofilin) works in concert with a protein that binds to filament ends (Srv2/CAP) to produce an activity that is orders of magnitude stronger than the that of either protein alone.

Video of cofilin and Srv2/CAP collaborating

The work was funded by National Institutes of Health, National Science Foundation MRSEC and Simons Foundation grant.

 Basketball, Dancing Proteins, and Life-saving Drugs

Dorothee Kern, Brandeis Magazine article

Dorothee Kern (center) with students in her Brandeis lab. (Image: Mike Lovett)

The Fall 2019 issue of Brandeis Magazine features a cover story on Professor of Biochemistry and HHMI Investigator Dorothee Kern.  The article describes Kern’s trajectory from her youth and education in the former East Germany to her current research and teaching at Brandeis to her co-founding of Relay Therapeutics, a Cambridge company pioneering new approaches to anti-cancer drug discovery.


Jeff Gelles elected to American Academy of Arts and Sciences

Jeff Gelles, 2019 AAAS recipient

credit: Heratch Ekmekjian

Jeff Gelles, the Aron and Imre Tauber Professor of Biochemistry and Molecular Pharmacology, has been elected to the American Academy of Arts and Sciences. He was among the  more than 200 outstanding individuals that were elected to the Academy in 2019 and announced on April 17.

The Gelles lab studies “little engines” or the nanometer-sized machines made of protein, RNA, and DNA molecules that carry out the essential processes in living cells.  The lab uses single-molecule light microscopy methods to study the functional mechanisms of these macromolecular complexes in cytoskeletal function, transcription and transcription regulation, and RNA processing.

Founded in 17890, the Academy recognizes the outstanding achievements of individuals in academia, the arts, business, government, and public affairs.

Read more: Amacad.org, BrandeisNow





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