Visualizing a protein decision complex in actin filament length control

Seen at the Gelles Lab Little Engine Shop blog this week, commentary on a new paper in Nature Communicationspublished in collaboration with the Goode Lab and researchers from New England Biolabs.

“Single-molecule visualization of a formin-capping protein ‘decision complex’ at the actin filament barbed end”

Regulation of actin filament length is a central process by which eukaryotic cells control the shape, architecture, and dynamics of their actin networks. This regulation plays a fundamental role in cell motility, morphogenesis, and a host of processes specific to particular cell types. This paper by recently graduated [Biophysics and Structural Biology] Ph.D. student Jeffrey Bombardier and collaborators resolves the long-standing mystery of how formins and capping protein work in concert and antagonistically to control actin filament length. Bombardier used the CoSMoS multi-wavelength single-molecule fluorescence microscopy technique to to discover and characterize a novel tripartite complex formed by a formin, capping protein, and the actin filament barbed end. Quantitative analysis of the kinetic mechanism showed that this complex is the essential intermediate and decision point in converting a growing formin-bound filament into a static capping protein-bound filament, and the reverse. Interestingly, the authors show that “mDia1 displaced from the barbed end by CP can randomly slide along the filament and later return to the barbed end to re-form the complex.” The results define the essential features of the molecular mechanism of filament length regulation by formin and capping protein; this mechanism predicts several new ways by which cells are likely to couple upstream regulatory inputs to filament length control.

Single-molecule visualization of a formin-capping protein ‘decision complex’ at the actin filament barbed end
Jeffrey P. Bombardier, Julian A. Eskin, Richa Jaiswal, Ivan R. Corrêa, Jr., Ming-Qun Xu, Bruce L. Goode, and Jeff Gelles
Nature Communications  6:8707 (2015)

The capping protein expression plasmid described in this article is available from Addgene.

Readers interested in this subject should also see a related article by Shekhar et al published simultaneously in the same journal.  We are grateful to the authors of that article for coordinating submission so that the two articles were published together.

DUB inhibitors _or_ why you should you eat your broccoli

Eat your broccoli!

We’re constantly bombarded by advice on which foods to eat or not eat, but skeptics among us often find compelling evidence for a convincing mechanism of how the foods promote health hard to come by – food has many components, and there are many different cells and metabolic pathways in those cells with which those components interact.

phenethyl isothiocyanate (a component of cruciferous vegetables)

phenethyl isothiocyanate (PEITC, a component of cruciferous vegetables)

Consider broccoli. It is well established that cruciferous vegetables have wide-ranging health benefits, apparently reducing cancer risks and lowering inflammation.  One set of phytochemicals responsible for the potent anti-cancer and anti-inflammatory properties are called isothiocyanates or ‘ITCs’.  It is now four decades since the discovery of ITCs, yet a molecular understanding of what ITCs do in a cell has proven elusive.

In a paper published this month in Cancer Research, Brandeis research scientist Ann Lawson, working in Liz Hedstrom’s laboratory, together with graduate students Marcus Long (Biochem) and Rory Coffey (Mol Cell Biol) and scientists from UbiQ and from Boston College, has shown that ITCs block the action of deubiquitinating enzymes (DUBs),  including the tumorigenesis-associated enzymes USP9x and UCH37, at physiologically relevant concentrations and time scales.

DUB inhibition provides a simple, unifying explanation that can account for many of the diverse health effects of ITCs. Understanding of how ITCs work at the molecular level may, one day, lead to new drug therapies for illnesses such as cancer, chronic inflammation, and neurodegenerative diseases.

Are you ready for your broccoli now? Me, I think I’ll have some kale sprouts.

Lawson AP, Long MJ, Coffey RT, Qian Y, Weerapana E, El Oualid F, Hedstrom L. Naturally occurring isothiocyanates exert anticancer effects by inhibiting deubiquitinating enzymes. Cancer Res. 2015

Hampton University & Brandeis Promote Diversity in the Sciences

Hampton University and Brandeis University have formed a new initiative called the Partnership for Research and Education in Materials (PREM). Using a 5-year, $3 million grant from the National Science Foundation, the  two universities have joined forces to foster interest in research science in under-represented groups of undergraduates.

A joint Pathway to Professorship (PtP) program will offer a path for under-represented research assistant professors to advance their research and possibly reach a tenure-track professorship at Brandeis or Hampton. These unique training positions could be filled by applicants in most disciplines including Biology, Chemistry, Physics, and Engineering. They involve one-year residences at Brandeis and Hampton Universities. Recruiting has started – interested applicants should start at the Hampton Career Opportunities website.

Brandeis’ 1st Innovation Showcase to be held 11/3/15


How is Brandeis changing the world? Brandeis’ first Innovation Showcase will feature poster presentations by the recipients of Brandeis’ SPARK and SPROUT awards. From 12pm-3pm on November 3rd at the Shapiro Science Center Atrium at the Brandeis Campus located in Waltham, MA.   Join us!


Pairs of Supermassive Black Holes May Be Rarer Than Earlier Thought

Image by David Roberts

Image by David Roberts

Recent research by David H. Roberts, William R. Kenan, Jr. Professor of Astrophysics at Brandeis, has shown that pairs of supermassive black holes at the centers of galaxies are less common than previously thought. This suggests that the level of gravitational radiation from such systems is lower than earlier predicted. This work was in collaboration with Lakshmi Saripalli and Ravi Subrahmanyan of the Raman Research Institute in Bangalore, and much of the work was done by Brandeis undergraduate students Jake Cohen and Jing Liu. It has recently been published in a pair of papers in the Astrophysical Journal Supplements and Astrophysical Journal Letters.

Gravitational waves are ripples in space-time predicted by Einstein’s 1915 General Theory of Relativity. Propagating at the speed of light, they are produced in astrophysical events such as supernovae and close binary stars.

No direct experimental evidence of the existence of gravitational waves has been found to date. We know that they exist because they sap energy from the orbits of binary systems, and using ultra-precise radio astronomy it has been shown that the changes in binary orbits of pairs of pulsars (magnetized neutron stars) are precisely as predicted by General Relativity. Hulse and Taylor were awarded the Nobel Prize in Physics for their contributions to this work.

The largest source of gravitational waves is expected to be the coalescence of pairs of supermassive black holes in the centers of large galaxies. We know today that galaxies grow by mergers, and that every galaxy harbors a massive black hole at its center, with mass roughly proportional to the galaxy’s mass. When two massive galaxies merge to form a larger galaxy, it will contain a pair of black holes instead of a single one. Through a process involving the gravitational scattering of ordinary stars the two black holes migrate toward each other and eventually coalesce into a single even more massive black hole. The process of coalescence involves “strong gravity,” that is, it occurs when the separation of the two merging black holes becomes comparable to their Schwarzschild radii. Recent developments in numerical relativity have made it possible to study the coalescence process in the computer, and predictions may be made about the details of the gravitational waves that emerge. Thus direct detection of gravitational waves will enable tests of General Relativity not achievable any other way.

In order to predict the amount of gravitational radiation present in the Universe it is necessary to estimate by other methods the rate at which massive galaxies are colliding and their black holes coalescing. One way to do this is to examine the small number of radio galaxies that have unusual morphologies that suggest that they were created by the process of a spin-flip of a supermassive black hole due to its interaction with a second supermassive black hole. These are the so-called “X-shaped radio galaxies” (“XRGs”), and a naive counting of their numbers suggests that they are about 6% of all radio galaxies. Using this and knowing the lifetime of such an odd radio structure it is possible to determine the rate at which massive galaxies are merging and their black holes coalescing.

Roberts et al. re-examined this idea, and made a critical assessment of the mechanism of formation of XRGs. It turns out that other mechanisms can easily create such odd structures, and according to their work the large majority of XRGs are not the result of black hole-black hole mergers at all. They suggest as a result that the rate of supermassive black hole mergers may have been overestimated by a factor of three to five, with the consequence that the Universe contains that much less gravitational radiation than previously believed. In fact, recent results from searches for such gravitational waves have set upper limits below previous predictions, as might expect from this work.

For more information:


Casey Wade Receives Grant from ACS Petroleum Research Fund

prf_figure_CWadeAssistant Professor of Chemistry Casey Wade has been selected to receive a Doctoral New Investigator grant from the American Chemical Society Petroleum Research Fund for his proposal, “Metal-organic Framework Supported Pincer Complexes: Investigation of the Effects of Site Isolation and Secondary Environment.” The two year grant will support the development of improved heterogeneous catalysts for the production of petroleum-derived commodity and fine chemicals.   Wade and coworkers plan to incorporate reactive transition metal catalyst sites into the well-defined 3-dimensional porous structure of metal-organic frameworks (MOFs). While the porous MOF support can be used to tune and promote reactivity, the immobilization of catalytically active sites prevents undesired bimolecular decomposition pathways and facilitates catalyst separation, leading to greener and more sustainable catalytic processes.

Post written by Christine Thomas

Putting “umpolung” to work in synthesis of nitrogen-bearing stereocenters

Professor Li Deng‘s lab in the Brandeis Chemistry Department has recently published a high-profile paper in Nature, disclosing an important advance in the chemical synthesis of organic molecules containing nitrogen. Li Deng writeup 1

A great number of important drugs contain at least one nitrogen atom connected to a “stereogenic” carbon atom. Stereogenic carbons are connected to four different groups, making possible two different configurations called “R-” or “S-”. In synthesizing a drug, it can be disastrous if the product does not have the correct R/S configuration.  For instance, the morning-sickness drug Thalidomide caused birth defects in ~10,000 children because it was a mixture of R and S molecules.Li Deng writeup 2

Selective preparation of only R or only S molecules containing nitrogen is a major challenge in organic chemistry. Many recent approaches have formed such stereocenters by use of an electron rich “nucleophile” to attack an electron poor “imine”. Deng is now the first to report an unconventional strategy in which the polarity of the reaction partners is reversed. In the presence of base and a creatively designed catalyst, the imine is converted into an electron rich nucleophile, and can attack a variety of electrophiles. Deng’s catalysts are effective in minute quantities (as low as 0.01 % of the reaction mixture), and yield products with R- or S- purities of 95-98 %.

In addition to Professor Deng, authors on the paper included former graduate student Yongwei Wu PhD ’14, current Chemistry PhD student Zhe Li, and Chemistry postdoctoral associate Lin Hu.

Wu Y, Hu L, Li Z, Deng L. Catalytic asymmetric umpolung reactions of imines. Nature. 2015;523(7561):445-50. (commentary)

New Faculty Member Joins the Physics Department

A new faculty member is joining the Physics department starting on January 1, 2016.

W. Benjamin RogersW. Benjamin (Ben) Rogers is currently a research associate in Applied Physics at Harvard University under the supervision of Professor Vinothan Manoharan. Before coming to Harvard, he completed his Ph.D. in the Department of Chemical and Biomolecular Engineering at the University of Pennsylvania and his B.S. in Chemical Engineering from the University of Delaware.

Ben’s research focuses on developing quantitative tools and design strategies to understand and control the self-assembly of soft matter. He is interested in elucidating the role of specificity in complex self-assembly, designing responsive nanoscale materials by controlling phase transitions in colloidal suspensions, and understanding how coupled chemical reactions give rise to active materials, which can move, organize, repair, or replicate. At the intersection of soft condensed matter, biophysics, and DNA nanotechnology, his research utilizes techniques from synthetic chemistry, optical microscopy, micromanipulation, and statistical mechanics.

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