Dynamics of GreB-RNA polymerase interaction

Larry Tetone, Larry Friedman, and Melissa Osborne, and collaborators from the Gelles lab (Brandeis University) and the Landick lab (University of Wisconsin-Madison) used multi-wavelength single-molecule fluorescence methods to for the first time directly observe the dynamic binding and dissociation of an accessory protein with an RNAP during active transcript elongation.

Their findings are detailed in the recent paper “Dynamics of GreB-RNA polymerase interaction.” (PNAS, published online 1/30/2017).

Read more at The Little Engine Shop blog

Research Funding For Undergrads: MRSEC Summer Materials Undergraduate Research Fellowships

The Division of Science wishes to announce that, in 2017, we will offer seven MRSEC Summer  Materials Undergraduate Research Fellowships (SMURF) for Brandeis students doing undergraduate research, sponsored by the Brandeis Materials Research Science and Engineering Center.

The fellowship winners will receive $5,000 stipends (housing support is not included) to engage in an intensive and rewarding research and development program that consists of full-time research in a MRSEC lab, weekly activities (~1-2 hours/week) organized by the MRSEC Director of Education, and participation in SciFest VII on Aug 3, 2017.

The due date for applications is February 27, 2017, at 6:00 PM EST.

To apply, the application form is online and part of the Unified Application: https://goo.gl/9LcSpG (Brandeis login required).


Eligibility

Students are eligible if they will be rising Brandeis sophomores, juniors, or seniors in Summer 2017 (classes of ’18, ’19, and ’20). No prior lab experience is required. A commitment from a Brandeis MRSEC member to serve as your mentor in Summer 2017 is required though. The MRSEC faculty list is: http://www.brandeis.edu/mrsec/people/index.html

Conflicting Commitments
SMURF recipients are expected to be available to do full time laboratory research between May 30 – August 4, 2017. During that period, SMURF students are not allowed to take summer courses, work another job or participate in extensive volunteer/shadowing experiences in which they commit to being out of the lab for a significant amount of time during the summer. Additionally, students should not be paid for doing lab research during this period from other funding sources.

Application Resources
Interested students should apply online (Brandeis login required). Questions that are not answered in the online FAQ may be addressed to Steven Karel <divsci at brandeis.edu>.

The Benefits of Middle Age

Almost all our cells harbor a sensory organelle called the primary cilium, homologous to the better known flagella found in protists. Some of these cilia can beat and allow the cell to move (eg. in sperm), or move fluid (eg. cerebrospinal fluid) around them. However, other specialized cilia such as those found in photoreceptor cells and in our olfactory neurons function solely as sensory organelles, providing the primary site for signal reception and transduction. The vast majority of our somatic cells display a short and simple rod-like cilium that plays crucial roles during development and in adulthood. For instance, during development, they are essential for transducing critical secreted developmental signals such as Sonic hedgehog that is required for the elaboration of cell types in almost every tissue (eg. in brain, bones, muscles, skin). In adults, cilia are required for normal functioning of our kidneys, and primary cilia in hypothalamic neurons have been shown to regulate hunger and satiety.

Given their importance, it is not surprising that defects in cilia structure and function lead to a whole host of diseases ranging from severe developmental disorders and embryonic lethality to hydrocephalus (fluid accumulation in the brain), infertility, obesity, blindness, and polycystic kidney among others. Often these diseases manifest early in development resulting in prenatal death or severe disability, but milder ciliary dysfunction leads to disease phenotypes later in life.

Much is now known about how cilia are formed and how they function during development. However, surprisingly, how aging affects cilia, and possibly the severity of cilia-related diseases, is not well studied. A new study by postdocs Astrid Cornils and Ashish Maurya, and graduate student Lauren Tereshko from Piali Sengupta’s laboratory, and collaborators at University College Dublin and University of Iowa, begins to address this question using the microscopic roundworm C. elegans (pictured below). These worms display cilia on a set of sensory neurons; these cilia are built by mechanisms that are similar to those in other animals including in humans. Worms have a life span of about 2-3 weeks, thereby making the study of how aging affects cilia function quite feasible.

benefits-midage

They find that cilia structure is somewhat altered in extreme old age in control animals. However, unexpectedly, when they looked at animals carrying mutations that lead to human ciliary diseases, the severely defective cilia seen in larvae and young adults displayed a partial but significant recovery during middle-age, a period associated with declining reproductive function. They went on to show that the heat-shock response and the ubiquitin-proteasome system, two major pathways required for alleviating protein misfolding stress in aging and neurodegenerative diseases, are essential for this age-dependent cilia recovery in mutant animals. This restoration of cilia function is transient; cilia structure becomes defective again in extreme old age. These results suggest that increased function of protein quality control mechanisms during middle age can transiently suppress the effects of some mutations in cilia genes, and raise the possibility that these findings may help guide the design of therapeutic strategies to target specific ciliary diseases. Some things can improve with aging!

Irving Epstein has been named AAAS Fellow

irving-epstein

In recognition of his contribution to the study of oscillating chemical reactions, Irving Epstein, the Henry F. Fischbach Professor of Chemistry, has been selected as a Fellow in the American Association for the Advancement of Science (AAAS).

Epstein, who in his 45 years at Brandeis has served as Provost and Dean of the Arts and Sciences, said he was honored to receive the award from the AAAS. “I’m delighted and grateful for the recognition,” he said. “It’s always nice to be appreciated by fellow scientists.”

 

Amy Lee Joins Biology Faculty

On August 1, Amy Lee joined the Biology department as an Assistant Professor. Previously, Amy was an American Cancer Society Postdoctoral Scholar in Jamie Cate’s lab at University of California, Berkeley. She received her Ph.D. in Virology from Harvard University in Sean Whelan’s lab and her Bachelors of Science in Biology from Massachusetts Institute of Technology.

Stx.key

eIF3d structure, see Figure 2 at http://rdcu.be/jzDD

Amy’s research focuses on understanding how gene regulation shapes cell growth and differentiation, and how dysregulation leads to human diseases like carcinogenesis and neurodegeneration. She is interested in discovering new mechanisms of mRNA translation initiation and novel functions of RNA-binding proteins and eukaryotic translation factors. Her research combines genome-wide and computational approaches together with molecular genetics, cell biology, biochemistry, and structural biology techniques.

Amy recently published a paper in Nature together with the Jamie Cate, Jennifer Doudna, and Philip Kranzusch describing the discovery of a new translation pathway that controls the production of proteins critical to regulating the growth and proliferation of cells. Cancer is characterized by uncontrolled cell growth, which means the protein production machinery goes into overdrive to provide the building materials and control systems for new cells. Hence, biologists for decades have studied the proteins that control how genes are transcribed into mRNA and how the mRNA is read and translated into a functioning protein. One key insight more than 40 years ago was that a so-called initiation protein must bind to a chemical handle on the end of each mRNA to start it through the protein manufacturing plant, the ribosome. Until now, this initiation protein was thought to be eIF4E (eukaryotic initiation factor 4E) for all mRNAs.

Amy and her colleagues discovered that for a certain specialized subset of mRNAs – most of which have been linked somehow to cancer – initiation is triggered by a different protein, called eIF3d. The finding was a surprise because the protein is part of an assembly of 13 proteins called eIF3 -eukaryotic initiation factor 3 – that has been known and studied for nearly 50 years, and no one suspected its undercover role in the cell. This may be because eIF3’s ability to selectively control mRNA translation is turned on only when it binds to the set of specialized mRNAs. Binding between eIF3 and these mRNAs opens up a pocket in eIF3d that then latches onto the end-cap of mRNA to trigger the translation process. Subsequent X-ray crystallography of eIF3d revealed the structural rearrangements that must occur when eIF3 binds to the mRNA tag and which open up the cap-binding pocket. eIF3d thus presents a promising new drug target in cancer, as a drug blocking this binding protein could shut off translation of only the growth-promoting proteins and not other life-critical proteins inside the cell.

Lee AS, Kranzusch PJ, Doudna JA, Cate JH. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature. 2016.

 

Using computer simulations to model bacterial microcompartment assembly

Bacterial microcompartments are protein shells found in bacteria that surround enzymes and other chemicals required for certain biological reactions.  For example, the carboxysome is a type of microcompartment that enables bacteria to convert the products of photosynthesis into sugars (thus taking carbon out of the atmosphere).  During the formation of a microcompartment, the outer protein shell assembles around hundreds of enzymes and chemicals required for the reaction.  Because the intermediates in this assembly process are small and short-lived, it is hard to study in detail using experiments. It is therefore useful to develop computational models that can help explain how proteins collect the necessary cargo, and then assemble into an ordered shell with the cargo on the inside.  The videos in this post show some examples of computer simulations of a model for bacterial microcompartment assembly, with each video corresponding to a different set of parameters that control the strengths of interactions among the proteins and cargo.

The study is described in the research article “Many-molecule encapsulation by an icosahedral shell” by Jason Perlmutter, Farzaneh Mohajerani, and Michael Hagan in eLife (eLife 2016;10.7554/eLife.14078).

Video 1: Multistep assembly of a microcompartment encapsulating hundreds of molecules (I) video1
Video 2: Multistep assembly of a microcompartment encapsulating hundreds of molecules (II)  video2
Video 3: Assembly of a microcompartment and encapsulation of hundreds of diffuse cargo molecules  video3

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