European Integrated Structural Biology Infrastructure Launching; How Cells Brace Themselves for Starvation; A Unique On/Off Switch for Hormone Production

European Integrated Structural Biology Infrastructure Launching

The Weizmann Institute is One of Seven “Instruct” Core Centres

Major transformations in biomedical science are on the horizon with the establishment of the world-class Integrated Structural Biology Infrastructure (Instruct) in support of European biomedical research.

The European Strategy Forum of Research Infrastructures (ESFRI) is involved in establishing about 40 such infrastructures, seven of them in biomedical sciences. Instruct is one such biomedical project, whose aim is to provide pan-European user access to state-of-the-art equipment, technologies, and manpower in cellular structural biology. This will allow Europe to maintain a competitive edge and play a leading role in this vital research area.

The Weizmann Institute of Science, together with Tel Aviv University, has been chosen as one of the seven Core Centres, joining prestigious institutions in the UK, Italy, France, and Germany.

“Structural biology is a scientific area in which Israeli scientists have been leading for many years, as evidenced by the Weizmann Institute’s Prof. Ada Yonath, who won a Nobel Prize in 2009 for her pioneering work on solving the structure of ribosomes,” says the Institute’s Prof. Joel Sussman, Director of Israel’s Instruct Core Centre.

Crucial to understanding how the living cell functions is knowledge of the three-dimensional structures of its proteins and nucleic acids, how these interact with one another, and their arrangement and dynamics within the cell. But no single discipline alone is able to decipher this. “In addition to the Weizmann Institute having developed world-class research programs in several of the disciplines relevant to Instruct, including electron microscopy, mass spectroscopy, x-ray crystallography, nuclear magnetic resonance (NMR), bioinformatics, and structural proteomics, the Israel Structural Proteomics Center (ISPC) has played a synergistic role in integrating and coordinating all these various disciplines,” says Prof. Sussman. The ISPC was established by scientists from the Weizmann Institute, with Prof. Sussman as its director, in order to increase the efficiency of protein structure determination.

Mirroring the philosophy of the ISPC, Instruct will merge the information obtained by the various structural biology methods and techniques in order to provide a dynamic picture of key cellular processes, both in vivo and in vitro, on all scales—from individual macromolecules through complexes and organelles to the whole cell. This knowledge will permit major advances in understanding and treating diseases.

“Instruct will allow laboratories throughout Europe to gain ready access to the most advanced facilities, technologies, and methodologies. Israeli scientists and their European counterparts will now have access to facilities they could only have dreamed of before,” says the Weizmann Institute’s Prof. Gideon Schreiber, Deputy Director of Israel’s Instruct Core Centre, as well as of the ISPC. “We hope this Core Centre will stimulate new collaborative research projects between laboratories throughout Europe with the Weizmann Institute and with other Israeli institutions, and also attract more graduate students, postdoctoral fellows, and visiting scientists from all over the world.”

Instruct will formally be launched at a signing ceremony in Brussels on February 23, 2012, and Weizmann Institute Vice President Prof. Haim Garty will be signing on behalf of the Weizmann Institute, Tel Aviv University, and the State of Israel.

More information can be found by visiting the Instruct Hub at www.structuralbiology.eu.

Prof. Joel Sussman’s research is supported by Mr. and Mrs. Yossie Hollander, Israel; the S. & J. Lurje Memorial Foundation; the Jean and Jula Goldwurm Memorial Foundation; the Samuel Aba and Sisel Klurman Foundation; the Bruce H. and Rosalie N. Rosen Family Foundation; and Mr. and Mrs. Howard Garoon, Glencoe, IL. Prof. Joel Sussman is the incumbent of the Morton and Gladys Pickman Professorial Chair in Structural Biology.

How Cells Brace Themselves for Starvation

Sugar, cholesterol, phosphates, zinc—a healthy body is amazingly good at keeping such vital nutrients at appropriate levels within its cells. From an engineering point of view, one all-purpose type of pump on the surface of a cell should suffice to keep these levels constant: When the concentration of a nutrient—for example, sugar—drops inside the cell, the pump mechanism could simply go into higher gear until the sugar levels are back to normal. Yet, strangely enough, such cells let in their nutrients using two types of pump: One is active in “good times,” when a particular nutrient is abundant in the cell’s environment; the other is a “bad-times” pump that springs into action only when the nutrient becomes scarce. Why does the cell need this dual mechanism?

A new Weizmann Institute study, reported in Science, might provide the answer. The research was conducted in the lab of Prof. Naama Barkai of the Department of Molecular Genetics by postdoctoral fellow Dr. Sagi Levy and graduate student Moshe Kafri, with lab technician Miri Carmi.

It had been known for a while that when the levels of phosphate or zinc drop in the surroundings of a yeast cell, the number of “bad-times” pumps on the cell surface soars up to a hundred-fold. When phosphate or zinc becomes abundant again, the “bad-times” pumps withdraw while the “good-times” pumps return to the cell surface in large numbers.

In their new study, the scientists discovered that cells which repress their “bad-times” pumps when a nutrient is abundant were much more efficient at preparing for starvation and at recovering afterwards than the cells that had been genetically engineered to avoid this repression. The conclusion: The “good-times” pumps apparently serve as a signaling mechanism that warns the yeast cell of approaching starvation. Such advance warning gives the cell more time to store up on the scarce nutrient; the thorough preparation also helps the cell start growing faster once starvation is over.

Thus, the dual-pump system appears to be part of a regulatory mechanism that allows the cell to deal effectively with fluctuations in nutrient supply. This clever mechanism offers the cell survival advantages that could not be provided by just one type of pump.

If these findings prove to be applicable to human cells, they could explain how our bodies maintain adequate levels of various nutrients in tissues and organs. Understanding the dual-pump regulation could be crucial because it might be defective in various metabolic disorders.

Prof. Naama Barkai’s research is supported by the Helen and Martin Kimmel Award for Innovative Investigation; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Carolito Stiftung; Lorna Greenberg Scherzer, Canada; the estate of John Hunter; the Minna James Heineman Stiftung; the European Research Council; and the estate of Hilda Jacoby-Schaerf. Prof. Barkai is the incumbent of the Lorna Greenberg Scherzer Professorial Chair.

A Unique On/Off Switch for Hormone Production

When we sense a threat, the brain center responsible for responding goes into gear, setting off a chain of biochemical reactions that lead to the release of cortisol from our adrenal glands.

Dr. Gil Levkowitz and his team in the Department of Molecular Cell Biology have now revealed a new kind of “on/off” switch in the brain for regulating the production of a main biochemical signal from the brain that stimulates cortisol release in the body. This finding, which was recently published in Neuron, may be relevant to research into a number of stress-related neurological disorders.

This signal is corticotropin releasing hormone (CRH). CRH is manufactured and stored in special neurons in the hypothalamus. Within this small region of the brain the danger is sensed, the information is processed, and the orders to go into stress-response mode are sent out. As soon as the CRH-containing neurons have depleted their supply of the hormone, they are already receiving the directive to produce more.

The research, which used zebrafish as a model, was spearheaded by Dr. Liat Amir-Zilberstein, together with Drs. Janna Blechman, Adriana Reuveny, and Natalia Borodovsky, as well as Maayan Tahor. The team found that a protein called Otp is involved in several stages of CRH production. In addition to directly activating the genes encoding CRH, Otp also regulates the production of two different receptors on the neurons’ surface for receiving and relaying CRH production signals—in effect, on and off switches.

The team found that both receptors are encoded in a single gene. To get two receptors for the price of one, Otp regulates a gene-editing process known as alternative splicing, in which some of the elements in the sequence encoded in a gene can be “cut and pasted” to make slightly different “sentences.” In this case, it generates two variants of a receptor called PAC1: The short version produces the on receptor; the long version, containing an extra sequence, encodes the off receptor. The researchers found that as the threat passed and the supply of CRH was replenished, the ratio between the two types of PAC1 receptor on the neurons’ surface gradually changed from more on to mostly off. In collaboration with Drs. Laure Bally-Cuif and William Norton of the Institute of Neurobiology Alfred Fessard at the Centre National de la Recherche Scientifique (CNRS) in France, the researchers showed that blocking the production of the long receptor variant causes an anxiety-like behavior in zebrafish.

Together with Drs. Alon Chen and Yehezkel Sztainberg of the Weizmann Institute’s Department of Neurobiology, Dr. Levkowitz’s team found the same alternatively spliced switch in mice. This conservation of the mechanism through the evolution of fish and mice implies that a similar means of turning CRH production on and off exists in the human brain.

Faulty switching mechanisms may play a role in a number of stress-related disorders. The action of the PAC1 receptor has recently been implicated in post-traumatic stress disorder (PTSD), as well as in schizophrenia and depression. Malfunctions in alternative splicing have also been associated with epilepsy, mental retardation, bipolar disorder, and autism.

Dr. Gil Levkowitz’s research is supported by the estate of Lore Lennon; the Kirk Center for Childhood Cancer and Immunological Disorders; and the Irwin Green Alzheimer’s Research Fund. Dr. Levkowitz is the incumbent of the Tauro Career Development Chair in Biomedical Research.

Dr. Alon Chen's research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Nella and Leon Benoziyo Center for Neurological Diseases; the European Research Council; Roberto and Renata Ruhman, Brazil; Martine Turcotte and Friends, Canada; Mark Besen and the Pratt Foundation, Australia; the estate of Nathan Baltor; the estate of Lola Asseof; and the Women's Health Research Center, funded by the Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the Harry and Jeanette Weinberg Women's Health Research Endowment, and the Oprah Winfrey Biomedical Research Fund. Dr. Chen is the incumbent of the Philip Harris and Gerald Ronson Career Development Chair.