Seeing key hinges in the lever arm of myosin at the atomic level

In this week’s on-line issue of the Proceedings of the National Academy of Sciences (PNAS), Brandeis researchers Jerry H. Brown, V. S. Senthil Kumar, Elizabeth O’Neall-Hennessey, Ludmila Reshetnikova, and Michelle Nguyen-McCarty ’10, together with Professors Andrew Szent-Györgyi and Carolyn Cohen, and Brookhaven National Laboratory researcher Howard Robinson, reveal the existence of a pair of major new hinges in the muscle protein myosin.

Muscle consists of myosin-containing thick filaments with projections, i.e. myosin heads, that exert force on actin-containing thin filaments during contraction. Previous crystal structures of the myosin head from bay scallop striated muscles and vertebrate muscles have already shown how this motion is produced by the amplification of small conformational changes about hinges in the motor domain (MD) by the so-called lever arm, which consists of the converter and elongated light chain binding domain (LCD).  Just like a baseball bat or other lever arms we are all familiar with in the “real world”, this LCD of myosin has appeared to be relatively rigid in these crystal structures, as it needs to be to transmit force effectively. But it has also long been expected that in muscle the myosin head, including its lever arm, is likely to contain elastic elements so that force can be produced under various strains.

(Left) Schematic of a myosin molecule and (right) the two conformations of the heavy chain portion of the LCD.

The Brandeis researchers originally set out to crystallize a myosin LCD corresponding to that from the catch muscle of sea scallop because it contains a specialized sequence whose structure was predicted to give insight into how muscle contraction of smooth muscles is turned on and off. Remarkably, however, as described in the PNAS article, this LCD forms two different conformations in the crystal, about mechanically linked hinges in the part of the lever arm distal from the motor. For the first time — and quite unexpectedly— a potential major elastic element in the lever arm has been visualized at atomic resolution, one that allows the length of the lever arm to change by about 10%. Sequence comparisons strongly suggest that these specific hinges are likely to be found in the lever arms of all muscle myosins. These comparisons also indicate differences in the degree of flexibility about these hinges in the different myosins, perhaps helping to account for the different properties (e.g., speed of contraction) of different types of muscle.

This result may also be important for mechanical engineers. In 2009, one of the authors (JHB) wrote an article in American Scientist that expands the concept of biomimicry by describing potentially novel joints, switches, and other mechanical designs that can be derived from the structures of various proteins. The current results in the PNAS seem to add one more. As described by Olena Pylypenko and former Brandeis researcher Anne Houdusse in a commentary scheduled to accompany the print version of the PNAS article, the motion about the hinge of the myosin LCD resembles the motion of a foot relative to a leg about an ankle. A lever “arm” that can extend or compress about an “ankle” may thus be one more novel mechanical design that nature can teach us about.

Dr. James Haber is to be named the 2011 Thomas Hunt Morgan medal recipient

Much like the scientist after whom this prestigious award is named,  Jim Haber has spent his scientific career asking big questions about genetics with the help of a small organism.  Instead of the humble fruit fly employed by Thomas Morgan, Jim and his students use the even humbler baker’s yeast Saccharomyces cerevisiae to study the complicated mechanisms of DNA recombination and repair.

Angie Brooksby (www.atelierfige.com)

Packed inside each little yeast cell is approximately 6000 genes worth of DNA, and the cell’s molecular machinery works very hard to fix any mistakes that might get incorporated into the genetic code.  Such mistakes can be caused by ultraviolet irradiation, mutagenic chemicals, and may even arise during the process of DNA replication itself.  Understanding how the yeast cell copes with these blows to its genetic integrity, as well as the consequences of mistakes gone unfixed, has been the focus of the Haber lab for over 20 years– but you don’t have to take my word for it.

In addition to recognizing purely scientific accomplishments, the Thomas Hunt Morgan medal is awarded to scientists who have proven to be excellent mentors to the students they work with.  In the spring of 2008, former students and post-docs of the Haber lab gathered at Brandeis to participate in a symposium honoring Jim’s 60th birthday, and the turn-out made clear that a sizeable amount of those who worked with Jim have either gone on to start successful labs of their own or entered into post-doctoral positions in labs of good repute.

When asked to reflect on what it’s been like to work with Jim, recent Haber lab graduate Dr. Wade Hicks answered that Jim “was a great mentor for me because he was always available to listen and talk about science.”  When further pressed against the journalistic blade and asked if Jim hosts any great parties, Wade coughed up that  “[Jim] does host the annual Halloween/pumpkin carving party that all the lab members’ kids enjoy…  What’s better than pumpkins, large knives, kids, and alcoholic beverages!?”

And finally, Jim’s eager willingness to talk about science extends beyond his lab and into the larger Life Sciences community– and likely beyond that.  Graduate students at departmental social events would be wise to chat Jim up regarding their projects– not to mention their gardens, favorite books, wine recommendations, etcetera.  In addition to being a great scientist, Jim is an all-around Good Guy.

Congratulations, Dr. Haber!

For further press see:

The Justice

Brandeis NOW

Breast cancer drug inventor to receive 2010 Gabbay Award

Angela Brodie, Ph.D. from the University of Maryland Greenebaum Cancer Center will receive the 2010 Jacob Heskel Gabbay Award in Biotechnology and Medicine. The award, administered by the Rosenstiel Center at Brandeis, consists of a $15,000 cash prize and a medallion. Dr. Brodie will deliver the award lecture, Aromatase Inhibitors and Breast Cancer: Concept to Clinic, on October 12, 2010 at 4:00 pm in Gerstenzang 121.

Dr. Brodie pioneered the development of aromatase inhibitors, a new class of drugs widely used today to treat breast cancer. Aromatase is the key enzyme in estrogen biosynthesis. Aromatase inhibitors reduce the level of estrogen produced by the body that fuels the growth of breast cancer cells. Although tamoxifen is effective in treating breast cancer, the antiestrogen is a partial agonist as well as an antagonist and may not be optimally effective against breast cancer. By using a different approach, Dr. Brodie reasoned that compounds that inhibit the production of estrogen without having significant estrogenic activity themselves might be more effective in treating breast cancer.
Dr. Brodie began developing aromatase inhibitors with her husband Harry Brodie in the early 1970s. She showed that the most potent inhibitor identified, 4-hydroxyandrostenedione (4-OHA) was effective in suppressing estrogen levels and causing regression of mammary tumors in animal models. Subsequently, she collaborated with the Royal Marsden Hospital in London to evaluate 4-OHA in breast cancer patients. The researchers found that the aromatase inhibitor not only suppressed serum estrogen concentrations, but also reduced tumors in postmenopausal patients with advanced breast cancer who had relapsed from tamoxifen or other treatments. This first selective aromatase inhibitor came into worldwide use in the early 1990s from Novartis. Dr. Brodie’s pioneering studies paved the way for three other FDA approved aromatase inhibitors.

Dr. Brodie is currently investigating new strategies for treating hormone resistant breast cancer based on understanding the molecular mechanisms involved. Dr. Brodie is also investigating androgen synthesis inhibitors to treat prostate cancer. A novel compound developed by her group has recently started clinical trials.

From sequence to consequence: Petsko-Ringe lab celebration

From Sequence to Consequence: Celebrating 30 Years of Science with
Dagmar Ringe and Greg Petsko

June 18-19, 2010
8:30 a.m. – 5:00 p.m.
Shapiro Auditorium

On September 4, 1980, Drs. Dagmar Ringe and Greg Petsko entered into an official collaboration, and the scientific community has never been the same since.  Now, 30 years later, their joint lab at Brandeis University is putting together a symposium to celebrate their combined lifetimes of achievement.  This 2-day event features 20 speakers who either trained or collaborated with the lab, plus a dinner reception on Friday night.  Registration is now open to all members of the Brandeis community.  Details and registration can be found at http://www.bio.brandeis.edu/PRSymposium2010/.  The registration code is scc30.

Dagmar and Greg

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