Background

Voltage-dependent ion channels are allosteric pore-forming proteins that open and close in response to changes in membrane potential. This form of gating allows the selective flow of K+, Na+ and Ca2+ ions across the membrane and underlies the production of electrical impulses known as action potentials- transient fluctuations in the membrane voltage-that spread across the surface of the cell, allowing neuron, for example, to transmit electric signals very rapidly over their length.

The involvement of the modular voltage-gated potassium channels (Kv) channels in shaping action potentials is primarily based on the tight interaction between their voltage-sensing and pore domains. The efficient propagation of the action potential along the axon and its transmission to the neighboring neuron or muscle cells requires that high densities of Kv channel molecules be brought into spatial proximity at the synapse-the site for inter-cellular communication. This process, referred to as channel clustering, is mediated by an intrinsically-disordered C-terminal segment of certain Kv channels and involves the interaction with intracellular scaffold proteins.

In my lab we study structure-function aspects of Kv channel gating and clustering using a multidisciplinary approach that combines several complementary experimental routes including sequence, structural, biochemical, biophysical, spectroscopic, electrophysiological, electron microscopy, cell biology and whole organism-level developmental biology analyses.

The Kv channel protein further represents an excellent model for studying the features underlying allosteric communication networks in proteins. Long-range communication between distant functional elements is a fundamental property of many allosteric proteins. Information transfer between such elements may be achieved by propagation of conformational changes through a protein structure, induced by changes in chemical or electrical potential. In our lab, to unravel the mechanism underlying experimentally-determined features of energy transduction along allosteric communication trajectories, we employ a powerful thermodynamic coupling analysis (double-mutant cycles) combine with Kv channel gating measurements.

Current Projects

1. Conformational transitions underlying information transduction along allosteric communication networks of voltage-activated potassium channels.

2. Distinct thermodynamic pore properties of leak (background) and voltage-activated potassium channels underlie their unique roles in electrical signaling.

3. Intrinsically-disordered protein domain of voltage-activated potassium channel mediates its binding to scaffold proteins: Implication for synapse assembly, maintenance and function.

Recent Publications

O. Rapp and O. Yifrach (2019). Evolutionary and functional insights into the mechanism underlying body size-related adaptation of mammalian hemoglobin. Elife, e47640.

A.I. König, R. Sorkin, A. Alon, D. Nachmias, K. Dhara, G. Brand, O. Yifrach, E. Arbely, Y. Roichman and N. Elia (2020) Live cell single molecule tracking and localization microscopy of bioorthogonally labeled plasma membrane proteins. Nanoscale, 12, 3236-3248.

V. Nirenberg and O. Yifrach (2020) Bridging the molecular-cellular gap in understanding ion channel clustering. Front. Pharmacol., 10, 1644.


L. Lewin, E. Nssasra, E. Gullbary, U. Hadad, I. Orr and O. Yifrach (2020) Molecular and cellular correlates in Kv channel clustering: entropy-based regulation of cluster ion channel density. Sci. Rep. 10 :11304.

V. A. Nirenberg and O. Yifrach (2020) Flow and shortcuts along the Shaker channel slow inactivation gating cycle. J. Gen. Physiol. 152:e202012611.

Ph.D. Weizmann Institute of Science, 2001