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.

Jané Kondev wins the Lerman-Neubauer ’69 Prize for Excellence in Teaching and Mentoring

Kondev_labThe 2015 recipient of the Jeanette Lerman-Neubauer ‘69 and Joseph Neubauer Prize for Excellence in Teaching and Mentoring is Jané Kondev, Professor of Physics. This prize requires its recipient to be not only be an exceptional teacher, but also a person known to be an outstanding mentor and advisor.

Jané has advised first year students and majors, served on senior thesis and dissertation committees, and supervised undergrads, grads and post-docs working in his lab. Additionally, he had chaired the Physics department, served as chair and Undergraduate Advising Head of the Biological Physics program, and co-directed the Quantitative Biology graduate program. His courses include the first year seminar, “Nature’s Nanotechnology,” as well as “Advanced Introductory Physics,” “Biological Physics” and “Quantum Mechanics.”

Jané earned his BS at the University of Belgrade and his PhD at Cornell University, and a postdoc at Brown University, where he won two Excellence in Teaching Awards. The goal of his research at Brandeis is to develop quantitative models of biological structure and function that can be tested experimentally. His current projects include the study of cell-to cell variability in gene expression, homologous recombination in yeast, synthetic genetic circuits, and formin assisted actin assembly.

Jané’s research has been supported by grants from the National Institutes of Health, the National Science Foundation and the MIT Whitehead Institute. His co-authored undergraduate textbook, Physical Biology of the Cell, won the 2013 Society of Biology Book Award, and his articles have been published in such journals as the Physics Today, Genetics, Cell Reports, and Biophysics.

Students in his courses write:

“Jané is an awesome instructor. He really cares that the students understand the material.”

“I learned a lot from informal conversations with Professor Kondev, and I appreciate all the energy and passion that he brings to the classroom.”

 

3 Division of Science Undergrads Win 2015 Giumette Academic Achievement Awards

lab_imageThree of five Guimette Academic Achievement Awards were recently given to Division of Science sophomores, according to Meredith Monaghan, Academic Services.  Each award is worth $5000 per semester for the remaining four terms of study.  In order to qualify for consideration, applicants must be sophomores with at least a 3.50 GPA who are not already receiving other merit awards. All 2015 recipients have been named to the Dean’s list in every semester.

The Giumette Academic Achievement Award began in the 2004-05 academic year to recognize currently enrolled sophomores who have distinguished themselves by their outstanding scholarship and academic achievements at Brandeis. The Academic Achievement Awards have been re-named after Peter Giumette, in honor of his twenty years of service to Brandeis as the head of Student Financial Services.

The Division of Science Giumette recipients are:

Zoe Brown ’17 is double majoring in Neuroscience and Psychology and has worked as a research assistant in Professor Arthur Wingfield’s Memory and Cognition Lab. This experience led Zoe to an internship at McLean hospital, where she works in the Bipolar and Schizophrenia division. Zoe will be a Bauer Foundation Summer Undergraduate Research Fellow in the Wingfield lab this summer. After graduating from Brandeis, Zoe plans to enter a Ph.D. program in either neuroscience or psychology and hopes to work in clinical neuropsychology, research, or teaching.

Kahlil Oppenheimer ’17 is double majoring in Computer Science and Mathematics. He serves as both a Teaching Assistant and an Undergraduate Department Representative for the Computer Science department. He has worked as an intern for both Draper Laboratories and HP Vertica, where he has utilized his academic knowledge in a real-world setting. Kahlil will be a software engineering intern at Kayak this summer and hopes to continue to explore both applied and abstract mathematics.

Leah Shapiro ’17 is majoring in both Biological Physics and Mathematics. Leah has been conducting independent research with Professors Jané Kondev (Physics) and Jeff Gelles (Biochemistry), on an interdisciplinary project investigating gene regulation and expression.  This summer Leah will be participating in research at the Yang Laboratory at the University of Michigan.

See story on BrandeisNow.

Chromosome Tethering in Yeast

On July 14, 2014, PLOS ONE  published a paper from the Haber and Kondev labs. The paper, Effect of chromosome tethering on nuclear organization in yeast, was authored by Baris Avsaroglu, Gabriel Bronk, Susannah Gordon-Messer, Jungoh Ham, Debra A. Bressan, James E. Haber, and Jane Kondev.

by Baris Avsaroglu

Chromosopone.0102474_350mes are folded into the cell nucleus in a non-random fashion. In yeast cells the Rabl model is used to describe the folded state of interphase chromosomes in terms of tethering interactions of the centromeres and the telomeres with the nuclear periphery. By combining theory and experiments, we assess the importance of chromosome tethering in determining the spatial location of genes within the interphase yeast nucleus. Using a well-established polymer model of yeast chromosomes to compute the spatial distributions of several genetic loci, we demonstrate that telomere tethering strongly affects the positioning of genes within the first 10 kb of the telomere. Further increasing the distance of the gene from the telomere reduces the effect of the attachment at the nuclear envelope exponentially fast with a characteristic distance of 20 kb. We test these predictions experimentally using fluorescently labeled genetic loci on chromosome III in wild type and in two mutant yeast strains with altered tethering interactions. For all the cases examined we find good agreement between theory and experiment. This study provides a quantitative test of the polymer model of yeast chromosomes, which can be used to predict long-ranged interactions between genetic loci relevant in transcription regulation and DNA recombination.

Dynamics of double-strand break repair


In a new paper in the journal Genetics, former Brandeis postdoc Eric Coïc and undergrads Taehyun Ryu and Sue Yen Tay from Professor of Biology Jim Haber’s lab, along with grad student Joshua Martin and Professor of Physics Jané Kondev, tackle the problem of understanding the dynamics of homologous recombination after double strand breaks in yeast. According to Haber,

The accurate repair of chromosome breaks is an essential process that prevents cells from undergoing gross chromosomal rearrangements that are the hallmark of most cancer cells.  We know a lot about how such breaks are repaired.  The ends of the break are resected and provide a platform for the assembly of many copies of the key recombination protein, Rad51.  Somehow the Rad51 filament is then able to facilitate a search of the entire DNA of the nucleus to locate identical or nearly identical (homologous) sequences so that the broken end can pair up with this template and initiate local copying of this segment to patch up the chromosome break.  How this search takes place remains poorly understood.

The switching of budding yeast mating type genes has been a valuable model system in which to study the molecular events of broken chromosome repair, in real time.  It is possible to induce synchronously a site-specific double-strand break (DSB) on one chromosome, within the mating-type (MAT) locus.  At opposite ends of the same chromosome are two competing donor sequences with which the broken ends of the MAT sequence can pair up and copy new mating-type sequences into the MAT locus.

Normally one of these donors is used 9 times more often than the other.  We asked if this preference was irrevocable or if the bias could be changed by making the “wrong” donor more attractive – in this case by adding more sequences to that donor so that it shared more and more homology with the broken ends at MAT.  We found that the competition could indeed be changed and that adding more homologous sequences to the poorly-used donor increased its use.


In collaboration with Jané Kondev’s lab we devised both a “toy” model and a more rigorous thermodynamic model to explain these results.  They suggest that the Rad51 filament carrying the broken end of the MAT locus collides on average 4 times before with the preferred donor region before it actually succeeds in carrying out the next steps in the process that lead to repair and MAT switching.

Dynamics of homology searching during gene conversion in Saccharomyces cerevisiae revealed by donor competition Eric Coïc , Joshua Martin, Taehyun Ryu, Sue Yen Tay, Jané Kondev and James E. Haber. Genetics. 2011 Sep 27 2011 Sep 27

Keith Cheveralls ’09, Daniel Beller ’10, and Netta Engelhardt ’11 awarded NSF Graduate Research Fellowships

Former physics majors Keith Cheveralls ’09 and Daniel Beller ’10 and current physics major Netta Engelhardt ’11 have been awarded the prestigious National Science Foundation Graduate Research Fellowship. The fellowship recognizes and supports outstanding graduate students in the US who have demonstrated exceptional promise in science research. Keith is currently a first year graduate student at UC Berkeley; while at Brandeis he did his senior thesis with Professor Jane Kondev and was a co-author on a paper that appeared last year in the Proceedings of the National Academy of Sciences. Dan, a first year graduate student at the University of Pennsylvania, completed his senior thesis at Brandeis with Professor Zvonimir Dogic and Professor Robert Meyer.  Currently, Dan is conducting research on liquid crystals in the group of Professor Randall Kamien at UPenn. Netta is currently doing her senior thesis with Professor Matthew Headrick, and is planning to attend graduate school in physics next year.

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