Suren A Tatulian

Title : Structural basis for ion channel formation by alzheimer’s disease-associated amyloid β peptides

Abstract:

The amyloid b (Ab) peptide is a major hallmark of Alzheimer’s disease (AD). The 42- and 40-amino acid peptides (Aβ_1-42, Aβ_1-40) are the most prevalent toxic Aβ species, but the pyroglutamylated forms (AβpE_3-42, AβpE_3-40) also occur in large quantities (10-50% of total Aβ) in AD brains and are hypertoxic. One of the mechanisms of Aβ cytotoxicity is disruption of cellular ionic homeostasis by permeabilization of plasma and intracellular membranes. The molecular mechanisms of ion channel formation and the diversity of channel conductance, including Aβ peptides’ structure and extent of membrane insertion, remain poorly understood. In this work, bilayer electrophysiology, atomic force microscopy, circular dichroism, fluorescence, and Fourier transform infrared spectroscopy are combined to characterize channel activities of the four most important Aβ peptides and to correlate them with the peptides’ structural features and lipid membrane insertion modes. Solvent-induced fluorescence splitting of tyrosine-10 has been uncovered and used to assess the degree of sequestration from the solvent through membrane insertion. Aβ_1-42 effectively embeds in lipid membranes, including the N-terminus harboring tyrosine-10, contains the largest fraction of β-sheet that forms a b-barrel-like structure, forms multi-subunit annular assemblies in lipid membranes, and displays well-defined step-like single channel features. In contrast, the other three peptides are membrane-attached peripherally, contain minimal b-sheet amount, form less regular assemblies, and produce a combination of step-like and burst-like membrane currents. These findings illuminate the structural basis of Aβ neurotoxicity through membrane permeabilization and may help develop new AD therapies that target Aβ-membrane interactions.

Audience Take Away Notes:

• The audience will learn that different forms of the Aβ peptide form ion-conducting channels in lipid membranes.
• In addition, the audience will learn that tyrosine fluorescence can be used to assess membrane insertion of proteins.
• This knowledge may help design new research projects aiming at the mechanism of channel formation by Aβ  peptides.
• This will help other researchers to explain their research data as well as to teach advanced courses.

Biography:

Dr. Tatulian received his BS in Physics from Yerevan University, Armenia, and his PhD in Biology from the Institute of Cytology, St. Petersburg, Russia, where he studied membrane transport. He joined the University of Virginia Medical School as a Research Associate in 1992 and was promoted to Assistant Professor in 1995. In 1999, he moved to the University of Kansas, Lawrence, KS, as Associate Professor. In 2001, he moved to the University of Central Florida where he was tenured and promoted to full Professor. Dr. Tatulian’s research focus is on protein structure and function and molecular mechanisms of disease.