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- 저자 : Safinya, C.R. (검색결과 13 건)
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Safinya, C.R.,Chung, P.J.,Song, C.,Li, Y.,Ewert, K.K.,Choi, M.C. Elsevier 2016 Advances in colloid and interface science Vol.232 No.-
In this review we describe recent studies directed at understanding the formation of novel nanoscale assemblies in biological materials systems. In particular, we focus on the effects of multivalent cations, and separately, of microtubule-associated protein (MAP) Tau, on microtubule (MT) ordering (bundling), MT disassembly, and MT structure. Counter-ion directed bundling of paclitaxel-stabilized MTs is a model electrostatic system, which parallels efforts to understand MT bundling by intrinsically disordered proteins (typically biological polyampholytes) expressed in neurons. We describe studies, which reveal an unexpected transition from tightly spaced MT bundles to loose bundles consisting of strings of MTs as the valence of the cationic counter-ion decreases from Z=3 to Z=2. This transition is not predicted by any current theories of polyelectrolytes. Notably, studies of a larger series of divalent counter-ions reveal strong ion specific effects. Divalent counter-ions may either bundle or depolymerize paclitaxel-stabilized MTs. The ion concentration required for depolymerization decreases with increasing atomic number. In a more biologically related system we review synchrotron small angle x-ray scattering (SAXS) studies on the effect of the Tau on the structure of paclitaxel-stabilized MTs. The electrostatic binding of MAP Tau isoforms leads to an increase in the average radius of microtubules with increasing Tau coverage (i.e. a re-distribution of protofilament numbers in MTs). Finally, inspired by MTs as model nanotubes, we briefly describe other more robust lipid-based cylindrical nanostructures, which may have technological applications, for example, in drug encapsulation and delivery.
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Safinya, Cyrus R.,Chung, Peter J.,Song, Chaeyeon,Li, Youli,Miller, Herbert P.,Choi, Myung Chul,Raviv, Uri,Ewert, Kai K.,Wilson, Leslie,Feinstein, Stuart C. American Chemical Society 2019 Langmuir Vol.35 No.48
<P>In this minireview, which is part of a special issue in honor of Jacob N. Israelachvili’s remarkable research career on intermolecular forces and interfacial science, we present studies of structures, phase behavior, and forces in reaction mixtures of microtubules (MTs) and tubulin oligomers with either intrinsically disordered protein (IDP) Tau, cationic vesicles, or the polyamine spermine (4+). Bare MTs consist of 13 protofilaments (PFs), on average, where each PF is made of a linear stack of αβ-tubulin dimers (i.e., tubulin oligomers). We begin with a series of experiments which demonstrate the flexibility of PFs toward shape changes in response to local environmental cues. First, studies show that MT-associated protein (MAP) Tau controls the diameter of microtubules upon binding to the outer surface, implying a shape change in the cross-sectional area of PFs forming the MT perimeter. The diameter of a MT may also be controlled by the charge density of a lipid bilayer membrane that coats the outer surface. We further describe an experimental study where it is unexpectedly found that the biologically relevant polyamine spermine (+4e) is able to depolymerize <I>taxol-stabilized</I> microtubules with efficiency that increases with decreasing temperature. This MT destabilization drives a dynamical structural transition where inside-out curving of PFs, during the depolymerization peeling process, is followed by reassembly of ring-like curved PF building blocks into an array of helical inverted tubulin tubules. We finally turn to a very recent study on pressure-distance measurements in bundles of MTs employing the small-angle X-ray scattering (SAXS)-osmotic pressure technique, which complements the surface-forces-apparatus technique developed by Jacob N. Israelachvili. These latter studies are among the very few which are beginning to shed light on the precise nature of the interactions between MTs mediated by MAP Tau in 37 °C reaction mixtures containing GTP and lacking taxol.</P> [FIG OMISSION]</BR>
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Safinya, Cyrus R.,Raviv, Uri,Needleman, Daniel J.,Zidovska, Alexandra,Choi, Myung Chul,Ojeda‐,Lopez, Miguel A.,Ewert, Kai K.,Li, Youli,Miller, Herbert P.,Quispe, Joel,Carragher, Bridget,Potter, WILEY‐VCH Verlag 2011 ADVANCED MATERIALS Vol.23 No.20
<P><B>Abstract</B></P><P>The review will describe experiments inspired by the rich variety of bundles and networks of interacting microtubules (MT), neurofilaments, and filamentous‐actin in neurons where the nature of the interactions, structures, and structure‐function correlations remain poorly understood. We describe how three‐dimensional (3D) MT bundles and 2D MT bundles may assemble, in cell free systems in the presence of counter‐ions, revealing structures not predicted by polyelectrolyte theories. Interestingly, experiments reveal that the neuronal protein tau, an abundant MT‐associated‐protein in axons, modulates the MT diameter providing insight for the control of geometric parameters in bio‐ nanotechnology. In another set of experiments we describe lipid‐protein‐nanotubes, and lipid nano‐ tubes and rods, resulting from membrane shape evolution processes involving protein templates and curvature stabilizing lipids. Similar membrane shape changes, occurring in cells for the purpose of specific functions, are induced by interactions between membranes and proteins. The biological materials systems described have applications in bio‐nanotechnology.</P>
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송채연,( Cyrus R. Safinya ),( Peter J. Chung ),( Youli Li ),( Kai K. Ewert ),( Myung Chul Choi ) 한국공업화학회 2017 한국공업화학회 연구논문 초록집 Vol.2017 No.1
We focus on the effects of multivalent cations, and separately, of microtubule-associated protein (MAP) Tau, on microtubule (MT) ordering (bundling), MT disassembly, and MT structure. Counter-ion directed bundling of paclitaxel-stabilized MTs is a model electrostatic system, which parallels efforts to understand MT bundling by intrinsically disordered proteins expressed in neurons. We describe studies, which reveal an unexpected transition from tightly spaced MT bundles to loose bundles consisting of strings of MTs as the valence of the cationic counter-ion decreases from Z=3 to Z=2. In a more biologically related system we review synchrotron small angle x-ray scattering (SAXS) studies on the effect of the Tau on the structure of paclitaxel-stabilized MTs.
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Zidovska, Alexandra,Ewert, Kai K.,Quispe, Joel,Carragher, Bridget,Potter, Clinton S.,Safinya, Cyrus R. Royal Society of Chemistry 2011 Soft matter Vol.7 No.18
<P>We report a study on the formation of block liposomes (BLs) and nanotubes from membranes comprising mixtures of membrane curvature-stabilizing multivalent cationic lipids MVL3(3+) and MVL5(5+) with neutral 1,2-dioleoyl-<I>sn-glycero</I>-3-phosphatidylcholine (DOPC). In conjunction with prior work on MVLBG2(16+), our experiments suggest that BL and nanotube formation is a general phenomenon in membranes containing multivalent lipids, thus enhancing the relevance of BLs for applications such as gene/drug storage and delivery or templating.</P> <P>Graphic Abstract</P><P>Mixtures of neutral and multivalent lipids (3+, 5+ and 16+; but not 1+) form block liposomes (BLs), in which distinct structures such as vesicles, bilayer tubes (nanotubes), and cylindrical micelles (nanorods) are connected together. BLs formed from different lipids show both common and unique features. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c1sm05481c'> </P>
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Shirazi, Rahau S.,Ewert, Kai K.,Silva, Bruno F. B.,Leal, Cecilia,Li, Youli,Safinya, Cyrus R. American Chemical Society 2012 Langmuir Vol.28 No.28
<P>Environmentally responsive materials (i.e., materials that respond to changes in their environment with a change in their properties or structure) are attracting increasing amounts of interest. We recently designed and synthesized a series of cleavable multivalent lipids (CMVLn, with <I>n</I> = 2–5 being the number of positive headgroup charges at full protonation) with a disulfide bond in the linker between their cationic headgroup and hydrophobic tails. The self-assembled complexes of the CMVLs and DNA are a prototypical environmentally responsive material, undergoing extensive structural rearrangement when exposed to reducing agents. We investigated the structural evolution of CMVL–DNA complexes at varied complex composition, temperature, and incubation time using small-angle X-ray scattering (SAXS) and wide-angle X-ray scattering (WAXS). A related lipid with a stable linker, TMVL4, was used as a control. In a nonreducing environment, CMVL–DNA complexes form the lamellar (L<SUB>α</SUB><SUP>C</SUP>) phase, with DNA rods sandwiched between lipid bilayers. However, new self-assembled phases form when the disulfide linker is cleaved by dithiothreitol or the biologically relevant reducing agent glutathione. The released DNA and cleaved CMVL headgroups form a loosely organized phase, giving rise to a characteristic broad SAXS correlation profile. CMVLs with high headgroup charge also form condensed DNA bundles. Intriguingly, the cleaved hydrophobic tails of the CMVLs reassemble into tilted chain-ordered L<SUB>β′</SUB> phases upon incubation at physiological temperature (37 °C), as indicated by characteristic WAXS peaks. X-ray scattering further reveals that two of the three phases (L<SUB>βF</SUB>, L<SUB>βL</SUB>, and L<SUB>βI</SUB>) constituting the L<SUB>β′</SUB> phase coexist in these samples. The described system may have applications in lipid-based nanotechnologies.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/langd5/2012/langd5.2012.28.issue-28/la301181b/production/images/medium/la-2012-01181b_0001.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/la301181b'>ACS Electronic Supporting Info</A></P>
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Bouxsein, Nathan F.,Leal, Cecí,lia,McAllister, Christopher S.,Ewert, Kai K.,Li, Youli,Samuel, Charles E.,Safinya, Cyrus R. American Chemical Society 2011 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.133 No.19
<P>We report the formation of liquid crystalline (LC) phases of short double-stranded DNA with nonpairing (nonsticky) overhangs, confined between two-dimensional (2D) lipid bilayers of cationic liposome–DNA complexes. In a landmark study (<I>Science</I><B>2007</B>, <I>318</I>, 1276), Nakata et al. reported on the discovery of strong end-to-end stacking interactions between short DNAs (sDNAs) with blunt ends, leading to the formation of 3D nematic (N) and columnar LC phases. Employing synchrotron small-angle X-ray scattering, we have studied the interplay between shape anisotropy-induced and DNA end-to-end interaction-induced N ordering for 11, 24, and 48 bp sDNA rods with single-stranded oligo-thymine (T) overhangs modulating the end-to-end interactions. For suppressed stacking interactions with 10-T overhangs, the volume fraction of sDNA at which the 2D isotropic (I)-to-N transition occurs for 24 and 48 bp sDNA rods depended on their length-to-width (<I>L</I>/<I>D</I>) shape anisotropy, qualitatively consistent with Onsager’s theory for the entropic alignment of rigid rods. As the overhang length is reduced from 10 to 5 and 2 T for 24 and 48 bp sDNA, the N-to-I transition occurs at lower volume fractions, indicating the onset of some degree of end-to-end stacking interactions. The 11 bp sDNA rods with 5- and 10-T overhangs remain in the I phase, consistent with their small shape anisotropy (<I>L</I>/<I>D</I> ≈ 1.9) below the limit for Onsager LC ordering. Unexpectedly, in contrast to the behavior of 24 and 48 bp sDNA, the end-to-end interactions between 11 bp sDNA rods with 2-T overhangs set in dramatically, and a novel 2D columnar N phase (N<SUB>C</SUB>) with finite-length columns formed. The building blocks of this phase are comprised of 1D stacks of (on average) four 11 bp DNA-2T rods with an effective <I>L</I><SUB>stacked</SUB>/<I>D</I> ≈ 8.2. Our findings have implications for the DNA-directed assembly of nanoparticles on 2D platforms via end-to-end interactions and in designing optimally packed LC phases of short anisotropic biomolecules (such as peptides and short-interfering RNAs) on nanoparticle membranes, which are used in gene silencing and chemical delivery.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2011/jacsat.2011.133.issue-19/ja202082c/production/images/medium/ja-2011-02082c_0010.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja202082c'>ACS Electronic Supporting Info</A></P>
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Leal, Cecí,lia,Ewert, Kai K.,Shirazi, Rahau S.,Bouxsein, Nathan F.,Safinya, Cyrus R. American Chemical Society 2011 Langmuir Vol.27 No.12
<P>The self-assembly of a custom-synthesized pentavalent cationic lipid (MVL5) and glycerol monooleate (GMO) with small interfering RNA (siRNA) results in the formation of a double-gyroid bicontinuous inverted cubic phase with colocalized lipid/siRNA domains as shown by synchrotron X-ray scattering and fluorescence microscopy. The high charge density (due to MVL5) and positive Gaussian modulus of the GMO-containing membranes confer optimal electrostatic and elastic properties for endosomal escape, enabling efficient siRNA delivery and effective, specific gene silencing.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/langd5/2011/langd5.2011.27.issue-12/la200679x/production/images/medium/la-2011-00679x_0003.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/la200679x'>ACS Electronic Supporting Info</A></P>
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Chung, Peter J.,Choi, Myung Chul,Miller, Herbert P.,Feinstein, H. Eric,Raviv, Uri,Li, Youli,Wilson, Leslie,Feinstein, Stuart C.,Safinya, Cyrus R. National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.47
<P><B>Significance</B></P><P>The microtubule-associated protein Tau is known to stabilize microtubules against depolymerization in neuronal axons, ensuring proper trafficking of organelles along microtubules in long axons. Abnormal interactions between Tau and microtubules are implicated in Alzheimer’s disease and other neurodegenerative disorders. We directly measured forces between microtubules coated with Tau isoforms by synchrotron small-angle X-ray scattering of reconstituted Tau–microtubule mixtures under osmotic pressure (mimicking molecular crowding in cells). We found that select Tau isoforms fundamentally alter forces between microtubules by undergoing a conformational change on microtubule surfaces at a coverage indicative of an unusually extended Tau state. This gain of function by longer isoforms in imparting steric stabilization to microtubules is essential in preventing microtubule aggregation and loss of function in organelle trafficking.</P><P>Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer’s. Here, we report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (<I>P</I>). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; Φ<SUB>Tau</SUB> = 1/10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to <I>P</I><SUB>B</SUB> ∼ 10,000–20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (<I>P</I><SUB>B</SUB> ∼ 1,000–2,000 Pa) over the same range. Remarkably, the abrupt increase in <I>P</I><SUB>B</SUB> observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < Φ<SUB>Tau</SUB> < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT–MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling because the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment.</P>
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