Dr. Hirsch Joel

Affiliation:Biochemistry, Faculty of life sciences
Sherman building
room 621
Tel:  (972)-3-6406211
Fax: (972)-3-6407931
Email: jhirsch@post.tau.ac.il
Personal Website:

Postal Address:Biochemistry
Faculty of life sciences

Tel Aviv University
Tel Aviv 69978

Research Interest

Broadly speaking, we are interested in the structural biology of cellular signaling.  We have focused on several systems that play key roles in signal transduction. Our goals are to obtain a mechanistic understanding of these molecules; how they interact, transmit and respond to various cues on the most basic level of physics and chemistry; and how this understanding can forge greater progress in comprehending the general biology to which they are pivotal.


Calcium signaling              

Calcium ions play a unique and critical role in cellular communication. As the Nobel laureate, Otto Loewi, who co-discovered the chemical basis for nerve transmission, said in 1959, “Ja, Kalzium, das ist alles!” Due to this role, a vast molecular apparatus for sensing and regulation of calcium’s movement has evolved. Movement of calcium ions from the extracellular space to inside the cell is prevented by the cellular membrane. The passage of calcium in a selective manner occurs by way of a family of proteins, namely voltage-dependent calcium channels. These channels couple electrical excitation of the cell to varied physiological processes including muscle contraction and secretion of hormones and neurotransmitters. The consequences of calcium channel activity in many tissues make them key drug targets. Hence, calcium channel blockers are widely used in the treatment of hypertension, angina, coronary spasm, and arrhythmias. Another class of calcium channel drugs is used against epilepsy and chronic pain.

Voltage-dependent calcium channels open upon depolarization of the plasma membrane, allowing inward flow of calcium ions from the extracellular milieu into the cell. The channels are multi-protein assemblies comprising four distinct subunits. The soluble beta subunit binds tightly to the membrane pore-forming subunit, alpha1. A region of the alpha1 subunit serves as beta’s primary anchor site. The  beta protein acts by both directing channels to the cellular membrane and by modulating gating. Upon my arrival here at TAU, we began a research program to examine the structure-function relationships of the beta subunit. Our recent publications include the three-dimensional structure determination of the beta protein by x-ray crystallography at atomic resolution. This technique represents an advanced and powerful physical method for discovering the three-dimensional structure of molecules ranging from the simplest to the most complex, containing hundreds of thousands of atoms. Importantly, we also solved the structure of beta in complex with its alpha1 subunit binding site. These results were based on a detailed experimental infrastructure involving recombinant expression of the relevant proteins, their purification and biochemical and biophysical characterization, using a variety of methods such as circular dichroism and fluorescence spectroscopies.

The structure details how the beta molecule contains protein-protein interaction modules, suggesting that this particular subunit is not only important as part of the calcium channel but may serve a role in related signaling pathways by associating with other proteins. Further, the findings indicate how beta may act as a “nursemaid” in calcium channel assembly. Finally, this first 3D picture of the calcium channel enables rational design of potential drugs that may regulate its activity and offers yet another approach to a molecular system with outstanding interest in medicine.


G-protein coupled receptor signaling

GPCR signaling is utilized by a wide variety of eukaryotic organisms to transmit signals from the environment. Membrane-bound heptahelical receptors e.g. rhodopsin are slowed by phosphorylation through the action of a receptor kinase. Arrestins then terminate receptor activity by binding the cytoplasmic surface of receptors, blocking continued interaction with G-proteins. Visual arrestin is highly selective for rhodopsin that has been both light-activated and phosphorylated and undergoes a conformational change, enabling high affinity binding to rhodopsin. Structural, biochemical and biophysical studies were the basis for a model of arrestin's molecular mechanism that I developed in collaboration with Seva Gurevich (Vanderbilt University School of Medicine) and others during my post-doctoral work. We have subsequently tested several aspects of this model, including identification of the flexible region in arrestin that enables the conformational switch.

Work initiated in my laboratory has focused on a set of constitutively active mutants. These mutants bind light-activated but not phosphorylated rhodopsin and thus give insight into how exactly arrestin becomes activated. Using fluorescence and CD spectroscopies under varying thermal or denaturant conditions and in conjunction with functional assays of the WT and mutant arrestins, we have outlined a working model for activation.

 In parallel, we have pursued a structural bioinformatic approach to understanding the arrestin family specifically using molecular phylogeny methods. This work has lead to conclusions regarding likely dimerization modes and the surfaces encoding binding binding partner specificity.


Other systems are under investigation, as well.


Selected Publications

No information available.