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Register a new userSingle-molecule force spectroscopy reveals structural differences of heparan sulfate chains during binding to vitronectin
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The syndecans represent an ongoing research field focused on their regulatory roles in normal and pathological conditions. Syndecans role in cancer progression becomes well-documented, implicating their importance in diagnosis and even proposing various cancer potential treatments. Thus, the characterization of the unbinding properties at the single molecules level will appeal to their use as targets for therapeutics. In our study, syndecan-1 and syndecan-4 were measured during the interaction with the vitronectin HEP II binding site. Our findings show that syndecans are calcium ion-dependent molecules that reveal distinct, unbinding properties indicating the alterations in heparin sulfate chain structure, possibly in the chain sequence or sulfation pattern. In that way, we suppose that HS chain affinity to ECM proteins may govern cancer invasion by altering syndecan ability to interact with cancer-related receptors present in the tumor microenvironment, thereby promoting the activation of various signaling cascades regulating tumor cell behavior.
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We derive approximate equations of motion for excited state dynamics of a multilevel open quantum system weakly interacting with light to describe fluorescence detected single molecule spectra. Based on the Frenkel exciton theory, we construct a model for the chlorophyll part of the LHCII complex of higher plants and its interaction with previously proposed excitation quencher in the form of the lutein molecule Lut 1. The resulting description is valid over a broad range of timescales relevant for single molecule spectroscopy, i.e. from ps to minutes. Validity of these equations is demonstrated by comparing simulations of ensemble and single-molecule spectra of monomeric LHCII with experiments. Using a conformational change of the LHCII protein as a switching mechanism, the intensity and spectral time traces of individual LHCII complexes are simulated, and the experimental statistical distributions are reproduced. Based on our model, it is shown that with reasonable assumptions about its interaction with chlorophylls, Lut 1 can act as an efficient fluorescence quencher in LHCII.
Voltage-gated sodium (Na$_mathrm{v}$) channels are responsible for the depolarizing phase of the action potential in most nerve cells, and Na$_mathrm{v}$ channel localization to the axon initial segment is vital to action potential initiation. Na$_mathrm{v}$ channels in the soma play a role in the transfer of axonal output information to the rest of the neuron and in synaptic plasticity, although little is known about Na$_mathrm{v}$ channel localization and dynamics within this neuronal compartment. This study uses single-particle tracking and photoactivation localization microscopy to analyze cell-surface Na$_mathrm{v}$1.6 within the soma of cultured hippocampal neurons. Mean-square displacement analysis of individual trajectories indicated that half of the somatic Na$_mathrm{v}$1.6 channels localized to stable nanoclusters $sim$230 nm in diameter. Strikingly, these domains were stabilized at specific sites on the cell membrane for >30 min, notably via an ankyrin-independent mechanism, indicating that the means by which Na$_mathrm{v}$1.6 nanoclusters are maintained in the soma is biologically different from axonal localization. Nonclustered Na$_mathrm{v}$1.6 channels showed anomalous diffusion, as determined by mean-square-displacement analysis. High-density single-particle tracking of Na$_mathrm{v}$ channels labeled with photoactivatable fluorophores in combination with Bayesian inference analysis was employed to characterize the surface nanoclusters. A subpopulation of mobile Na$_mathrm{v}$1.6 was observed to be transiently trapped in the nanoclusters. Somatic Na$_mathrm{v}$1.6 nanoclusters represent a new, to our knowledge, type of Na$_mathrm{v}$ channel localization, and are hypothesized to be sites of localized channel regulation.
One of the most intriguing results of single molecule experiments on proteins and nucleic acids is the discovery of functional heterogeneity: the observation that complex cellular machines exhibit multiple, biologically active conformations. The structural differences between these conformations may be subtle, but each distinct state can be remarkably long-lived, with random inter
Force and conductance were simultaneously measured during the formation of Cu-C60 and C60-C60 contacts using a combined cryogenic scanning tunneling and atomic force microscope. The contact geometry was controlled with submolecular resolution. The maximal attractive forces measured for the two types of junctions were found to differ significantly. We show that the previously reported values of the contact conductance correspond to the junction being under maximal tensile stress.
Single-molecule force spectroscopy has proven to be a powerful tool for studying the kinetic behavior of biomolecules. Through application of an external force, conformational states with small or transient populations can be stabilized, allowing them to be characterized and the statistics of individual trajectories studied to provide insight into biomolecular folding and function. Because the observed quantity (force or extension) is not necessarily an ideal reaction coordinate, individual observations cannot be uniquely associated with kinetically distinct conformations. While maximum-likelihood schemes such as hidden Markov models have solved this problem for other classes of single-molecule experiments by using temporal information to aid in the inference of a sequence of distinct conformational states, these methods do not give a clear picture of how precisely the model parameters are determined by the data due to instrument noise and finite-sample statistics, both significant problems in force spectroscopy. We solve this problem through a Bayesian extension that allows the experimental uncertainties to be directly quantified, and build in detailed balance to further reduce uncertainty through physical constraints. We illustrate the utility of this approach in characterizing the three-state kinetic behavior of an RNA hairpin in a stationary optical trap.
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