Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules (MTs) Cyrus R. Safinya, University of California-Santa, DMR 1101900.

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Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules (MTs) Cyrus R. Safinya, University of California-Santa, DMR Figure (Right) Cartoons show a microtubule (MT, assembled from  /  -tubulin dimers shown in red/blue, which stack to form protofilaments, PFs) and an unexpected depolymerizing transition in a taxol-stabilized MT in the presence of specific ions. (Left) Ion specific effects showing the range of concentrations for different ions for which taxol- stabilized MTs are stable (color coded arrows), and, ion concentrations (indicated by colored lines after arrows), beyond which taxol stabilized MTs have depolymerized. The data revealing stable versus depolymerized MTs were obtained using synchrotron small- angle-x-ray-scattering at the Stanford Synchrotron Radiation Laboratory. The observed trend is that the ion concentration at which MT depolymerization sets in decreases with increasing atomic number. The y-axis shows that the MT inner radius (R in MT ) does not change in the presence of all ions studied consistent with MTs with 13 protofilaments. (Relevant references: Needleman, D. J.; Ojeda-Lopez, M. A.; et al.: Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules. Faraday Discussions 2013, in press. Doi: /C3FD00063J; Ojeda-Lopez, M. A. et al.: Molecularly-Triggered Conformation Switch in Tubulin Leads to Inverted Protein Tubules. Nature Materials (under review). See Microtubules (MTs) are nanometer scale hollow cylindrical biological polyelectrolytes (cartoon in figure). MTs and their assemblies are key components in cell functions from providing tracks for the transport of cargo to forming the spindle apparatus in chromosome segregation. Here, we discovered that while bundling of taxol-stabilized MTs occurs for certain divalent cations above a critical ion concentration (e.g. Ca 2+, Sr 2+, Ba 2+ ), many divalent cations (Mg 2+, Mn 2+, Co 2+, and Zn 2+ ) preempt the bundling transition and depolymerize taxol-stabilized MTs in an ion-specific manner (see Figure). The significance of the work is that understanding the factors influencing the stability or disruption of the microtubule-cytoskeleton is very important because unintended MT depolymerization (i.e. not during mitosis) invariably leads to disruptions in organelle transport. Ion- specific transition Depolymer- ization of taxol- stabilized MT 26 nm MT Our findings are highly surprising given the known stabilizing effects of taxol, a cancer chemotherapy drug, which attaches to the  -subunit (from the inner lumen side of the MT) and stabilizes MTs. Numerous studies have shown that taxol promotes MT assembly and inhibits MT depolymerization.

Broader Impacts: Education and Outreach Research Training Cyrus R. Safinya, University of California-Santa, DMR Education: Undergraduate and graduate students, and postdoctoral scholars with backgrounds in materials science, physics, chemistry, and biology, are educated in methods to discover nature’s rules for assembling molecular building blocks in distinct shapes and sizes for particular functions. The learned concepts enable development of advanced materials for applications Outreach/Participation of undergraduate/ underrepresented students: The bottom photo shows Bretton Fletcher (an undergraduate student in physics at UCSB) next to his mentor Dr. Kai Ewert (an expert synthetic chemist and a Project Scientist in the Materials department at UCSB). Bretton is currently being trained in order to develop the skills to synthesize new cationic and neutral lipids for gene delivery and gene silencing applications. (For more information see The middle photo shows Cathrine (Cat) Keiner standing next to her mentor Peter Chung (physics PhD graduate student). Cat is an undergraduate student in Chemistry and Biochemistry at UCSB. Her experiments are designed to understand the biophysical functions of tau (a microtubule-associated-protein). Tau is involved in a range of biological functions, in particular, modulation of the dynamics of polymerization of tubulin (into microtubules, MTs) and inhibition of depolymerization of MTs. Cat participated in the RISE program and she will also be further researching in the group during the upcoming year. Bezawit B Sumner (top photo) is a Masters graduate student at Jackson State University working towards her Biology degree. Bezawit participated in UCSB’s RISE program (Research in Science and Engineering, summer 2013). Her project was centered around optical microscopy and x-ray diffraction studies of lipid-DNA complexes and mammalian cells. She was trained in these important techniques by her mentor Ramsey Majzoub (physics PhD graduate student, top photo).