Riboswitches and fluoride

Ronald Breaker (Yale and HHMI) gave an inspiring talk today to kick off this year’s Biochemistry-Biophysics Friday Lunchtime Pizza Talks series, discussing his lab’s work on Riboswitches: Biology’s Ancient Regulators. If you missed the talk, here’s a review that might help you catch up.

Breaker ended the talk by discussing the fluoride-sensing riboswitch, and pointing to the new avenues for research to which this called attention. Coincidentally(?), a new paper in PNAS is out today from Chris Miller‘s lab here at Brandeis on exactly that — take a look at Stockbridge et al., Fluoride resistance and transport by riboswitch-controlled CLC antiporters.

 

Tenure track faculty position, Biochemistry

The Department of Biochemistry at Brandeis University invites applications for a tenure-track faculty position, to begin Fall, 2013. We are searching for a creative scientist who will establish an independent research program and who in addition will maintain a strong interest in teaching Biochemistry at the undergraduate and graduate levels. The research program should address fundamental questions of biological, biochemical, or biophysical mechanism.

Brandeis University offers the rare combination of a vigorous research institution in a liberal-arts college setting. The suburban campus is located 20 minutes from Boston and Cambridge and is part of the vibrant community of academic and biotechnology centers in the Boston area.

The application should include a cover letter, curriculum vitae, statement of research accomplishments and future plans, and three letters of reference. Applications will be accepted only through https://academicjobsonline.org/ajo/jobs/1813. Additional inquiries may be directed to Chris Miller, Professor of Biochemistry (cmiller@brandeis.edu).

First consideration will be given to applications received by December 1, 2012. Brandeis University is an Equal Opportunity Employer, committed to building a culturally diverse intellectual community. We particularly welcome applications from women and minority candidates.

What a failed drug does (and is there hope for latrepirdine?)

Latrepirdine (Dimebon) was initially used as an antihistamine drug in Russia. It was later found to be neuroprotective, and entered phase II clinical trials in the US for both Alzheimer’s disease and Huntington’s disease. However, Dimebon failed in a US-based phase II replication trial of a prior successful Russian phase II trial of mild-to-moderate AD. Given the initial promise of the drug and split results,  as well as the lack of treatments for neurodegenerative diseases, there in is significant interest in understanding the underlying molecular mechanism(s) for the drug’s effects.

In a paper appearing this week in Molecular Psychiatry, Brandeis researchers in the Petsko-Ringe lab, including postdoc Shulin Ju and undergraduate Jessica Liken ’11, used yeast models of neurodegenerative disease associated proteins to show that Dimebon specifically protects yeast from the cytotoxiciy of α-synuclein, a protein involved in Parkinson’s disease. They further showed that protection is mediated through its up-regulation of autophagy pathway. In collaboration with Sam Gandy‘s group at Mount Sinai School of Medicine, these findings were further confirmed and validated in neuronal cell and animal models.

Given these observations, disparities in the contribution of α-synuclein to the neuropathology between the Russian and US Dimebon studies might also explain, at least in part, the inconsistency of the cognitive benefit in the two trials. If this speculation is correct, then it may be interesting to test for benefits of Dimebon in treating synucleinopathies such as Parkinson’s disease, Lewy body dementia, REM sleep disorder and/or multiple system atrophy.

see also: press release from Mt. Sinai Alzheimer’s Diesease Research Center

Steele JW (*), Ju S(*), Lachenmayer ML(*), Liken J, Stock A, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Protter AA, Martins RN, Ehrlich ME, Yue Z, Petsko GA, Gandy S. Latrepirdine stimulates autophagy and reduces accumulation of alpha-synuclein in cells and in mouse brain. Molecular psychiatry. 2012.

Steele JW(*), Lachenmayer ML(*), Ju S, Stock A, Liken J, Kim SH, Delgado LM, Alfaro IE, Bernales S, Verdile G, Bharadwaj P, Gupta V, Barr R, Friss A, Dolios G, Wang R, Ringe D, Fraser P, Westaway D, St George-Hyslop PH, Szabo P, Relkin NR, Buxbaum JD, Glabe CG, Protter AA, Martins RN, Ehrlich ME, Petsko GA, Yue Z, Gandy S. Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer’s mouse model. Molecular psychiatry. 2012.

Unraveling mutations in pediatric brain cancer

Medulloblastoma is the most common malignant brain tumor of childhood, with an overall mortality of 40 to 50 percent. Surviving children often have significant long-term cognitive and physical sequelae resulting from existing treatments. Therefore, identifying and understanding the genetic events that drive these tumors is critical for the development of more effective therapies.

In the 2 August issue of the journal Nature, Brandeis Biochemistry faculty member Daniel Pomeranz Krummel contributed his structural biological expertise in collaboration with colleagues at Children’s Hospital Boston, Dana-Farber Cancer Institute, Harvard University, the Broad Institute (MIT), Stanford and the Hospital for Sick Children in Toronto. The paper titled, “Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations,” unravels a landscape of mutations that are peculiar to medulloblastomas. This paper represents a landmark study of medulloblastomas. More specifically, Pomeranz Krummel’s collaborators noticed that a protein called DDX3X had numerous mutations in medulloblastoma. Pomeranz Krummel was able to create a structural model of DDX3X that provided insight into the functional significance of the critical mutations in children with medulloblastoma (below, image).

DDX3X is an ATP-dependent RNA helicase. RNA helicases are fascinating proteins that function to drive the restructuring of RNA and/or RNA-protein assemblies, and have proven to be of great importance in cancer biology and HIV research. Pomeranz Krummel’s long-standing interest is in RNA-protein interactions and application of methods to visualize the enzymes critical to processing of RNA in the human cell. Thus, thinking about the structure-function relationship of this RNA helicase DDX3X was a problem of much interest to Pomeranz Krummel. This collaboration involved forging links between basic and translational scientists, thus giving rise to promising new horizons of treatment options for children with medulloblastoma.

 

 

Brandeis grad students guest edit The Biochemist

Brandeis graduate students Kene Piasta (Biochemistry, PhD ’11), Dharia McGrew (Mol. Cell. Biology, PhD ’11) and Lena Webb (Mol. Cell. Biology, MS ’11) were recently rewarded with the chance to be guest editors for The Biochemist, the bi-monthly magazine for members of the Biochemical Society. The issue they produced, with articles covering “The Science of Sensation“, is now available. The issue covers the biology of the five senses people have (and one that people don’t have but fish do). All three students have moved on from Brandeis: Lena now edits scripts for the Journal of Visualized Experiments, Kene is a postdoc in Joseph Falke’s lab at U. Colorado, Boulder, studying bacterial two-component chemoreceptors, and Dharia is a science and technology policy fellow with the state of California.

Tenure-track faculty search in Biochemistry (2012)

The Department of Biochemistry at Brandeis University invites applications for a tenure-track faculty position at the rank of ASSISTANT PROFESSOR beginning Fall 2012.  We are searching for a creative scientist who will establish a vigorous independent research program and who also demonstrates a commitment to teaching.  The research program should address fundamental questions of biological and/or biochemical function at the molecular level.

Brandeis offers the rare combination of an internationally recognized research university in a small college setting.  The suburban campus is just 20 minutes from Boston and Cambridge and is part of the vibrant community of academic and biotechnology centers in the Boston area.

The candidate should submit a curriculum vitae and brief research proposal in Word or PDF format by email to biochemistrysearch@lists.brandeis.edu, or by post to:

Daniel D. Oprian
Chair Faculty Search Committee
c/o Maureen Ferrari
Department of Biochemistry, MS009
Brandeis University
Waltham, MA 02454-9110

The candidate should also arrange to have three letters of reference sent to the above address (email preferred).

First consideration will be given to applications received by December 31, 2011, but applications will be accepted until the position is filled.

Brandeis University is an Equal Opportunity Employer, committed to building a culturally diverse intellectual community, and strongly encourages applications from women and minority candidates.

A Little Freedom Makes a Big Difference

As enzymes evolve over time, proteins of similar structure acquire small sequence changes and acquire new activities. What are the key changes in an enzyme’s structure or mechanism that allow this to happen? Researchers from the Hedstrom lab, led by former postdoc Gregory Patton, in collaboration with researchers from the Karolinska Institute, investigated this question in the case of two proteins, inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate reductase (GMPR). The enzymes share similar structural features but carry out different reactions in a cell. Since the two enzymes are in opposing pathways, there could be severe consequences if the enzymes slip and carry out the ‘other’ reaction.

The results, published last month in Nature Cell Biology, argue strongly that the difference is based on the ability of the enzyme to switch between two conformations. A single crystal structure of human GMPR type 2 with IMP and NADPH fortuitously captures three different states, each of which mimics a distinct step in the catalytic cycle of GMPR, including states in which the cofactor (NAD or NADP) is either in an ‘in’ conformation poised for hydride transfer (below, right), or an ‘out’ conformation in which the cofactor is 6 Å from IMP (below, left).

Using mutagenesis along with kinetic experiments, the group demonstrates that the ‘out’ conformation is required for the deamination of GMP. The accessibility of this conformation at the key step in GMPR but not IMPDH seems to determine the two different outcomes — thus, the freedom of the enzyme and cofactor to carry out a conformational change determines the specificity.

An interesting question, looking at the pathways, is whether GMPR can ‘run in reverse’, catalyzing the direct amination of IMP to form GMP (and saving the cell some energy in the process).  Overexpression of GMPR does allow E. coli to survive in the absence of IMPDH and GMPS, demonstrating that GMPR-driven synthesis of GMP can support life.  Indeed, some modern organisms that live in ammonia-rich environments appear to obtain GMP by this strategy.  If life began in an ammonia rich environment as is often proposed, the ancestral purine biosynthetic pathways may have produced GMP via GMPR.

For more details, see the paper:  Patton GC, Stenmark P, Gollapalli DR, Sevastik R, Kursula P, Flodin S, Schuler H, Swales CT, Eklund H, Himo F, Nordlund P, Hedstrom L. Cofactor mobility determines reaction outcome in the IMPDH and GMPR (beta-alpha)(8) barrel enzymes. Nat Chem Biol. 2011.

Long receives HHMI fellowship to develop new protein degradation strategy

Marcus Long, a 3rd yr PhD student in the Graduate Program in Biochemistry who works in the Hedstrom Lab, has been awarded a Howard Hughes International Student Predoctoral Research Fellowship for 2011-2013. This award, which is open only to students at selected universities, is given to roughly 40 international students in the life sciences per year in the US. The receipt of this award reflects strongly on the quality of research conducted in Brandeis, and particularly the interdisciplinary approach taken by principal investigator, Prof. Liz Hedstrom. Application for the award requires a clear research plan, which in this instance involves a novel protein degradation strategy (called IMPED), which was pioneered by Prof Hedstrom and her laboratory. Marcus will play his part in a collaborative effort  (alongside lab mates Rory Coffey, Devi Gollapali and established Hedstrom Group collaborators) to understand the mechanism and limitations of this new methodology.

Mehmet Fisek (BS/MS ’08), an alumnus of the Marder lab and undergraduate Neuroscience program at Brandeis, was also among the 48 winners named. Mehmet is currently doing graduate research in Rachel Wilson’s lab in the Dept. of Neurobiology at Harvard, working on olfactory neurophysiology in Drosophila.

See also story at Brandeis NOW.

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