Parallel Dimers Research Articles

Near-field radiative heat transfer in graphene plasmonic nanodisk dimers

Near-field thermal radiation mediated by surface plasmons in parallel graphene nanodisk dimers is studied using a semianalytical model under the electrostatic approximation. The radiative heat transfer between two disks as a function of the distance between them in coaxial and coplanar configurations is first considered. Three regimes are identified and their extents determined using nondimensional analysis. When the edge-to-edge separation is smaller than the disk diameter, near-field coupling and surface plasmon hybridization lead to an enhancement of the radiative heat transfer by up to four orders of magnitude compared to the Planck blackbody limit. A mismatch in the disk diameters affects the plasmonic mode hybridization and can either diminish or enhance the near-field radiation. Destructive interference between eigenmodes that emerge when the relative orientation between disks is varied can induce a twofold reduction in the radiative heat transfer. In all configurations, the radiative heat transfer properties can be controlled by tuning the disk size/orientation, the substrate optical properties, and graphene's doping concentration and electron mobility.

An alternate mode of oligomerization for E. coli SecA

SecA is the ATPase of preprotein translocase. SecA is a dimer in solution and changes in its oligomeric state may function in preprotein translocation. The SecA-N68 construct, in which the C-terminal helical domains of SecA are deleted, was used to investigate the mechanism of SecA oligomerization. SecA-N68 is in equilibrium between monomers, dimers, and tetramers. Subunit interactions in the SecA-N68 tetramer are mediated entirely by unstructured regions at its N- and C-termini: when the termini are deleted to yield SecA-N68∆NC, the construct is completely monomeric. This monomeric construct yielded crystals diffracting to 2.6 Å that were used to solve the structure of SecA-N68, including the “preprotein crosslinking domain” (PPXD) that was missing from previous E. coli SecA structures. The SecA-N68 structure was combined with small angle X-ray scattering (SAXS) data to construct a model of the SecA-N68 tetramer that is consistent with the essential roles of the extreme N- and C-termini in oligomerization. This mode of oligomerization, which depends on binding of the extreme N-terminus to the DEAD motor domains, NBD1 and NBD2, was used to model a novel parallel and flexible SecA solution dimer that agrees well with SAXS data.

A new low temperature solid modification in 1-isothiocyanato-4-(trans‑4-propylcyclohexyl)benzene (3CHBT) probed by Raman spectroscopy and quantum chemical calculations

Raman spectra of 1-isothiocyanato-4-(trans 4-propylcyclohexyl)benzene (3CHBT) were studied in the region, 1450–2300cm−1 at twenty two different temperatures in the range, 83–293K in cooling and heating cycles. All bands in this region were critically evaluated in term of linewidth, peak position and relative intensity. Raman bands at ~2085cm−1 and ~2120cm−1 shows clear evidence of a solid modification through anomaly in temperature dependence peak positions and linewidths variation in the temperature range 173–203K. A detailed analysis of the variation of the linewidth and peak position of the two component bands leads to the conclusion that the molecular/dimer arrangement in crystalline packing changed between 173K and 203K. This solid modification was also analyzed at the molecular level. The ~2085cm−1 and ~2120cm−1 bands were corresponded as parallel and anti-parallel dimers of 3CHBT, which are identified as dimer I (D1) and dimer II (D2), respectively. The structures of both the dimers have been optimized by quantum chemical calculations employing density functional theoretic (DFT) methods.

Molecular basis of the microtubule-regulating activity of microtubule crosslinking factor 1.

The variety of microtubule arrays observed across different cell types should require a diverse group of proteins that control microtubule organization. Nevertheless, mainly because of the intrinsic propensity of microtubules to easily form bundles upon stabilization, only a small number of microtubule crosslinking proteins have been identified, especially in postmitotic cells. Among them is microtubule crosslinking factor 1 (MTCL1) that not only interconnects microtubules via its N-terminal microtubule-binding domain (N-MTBD), but also stabilizes microtubules via its C-terminal microtubule-binding domain (C-MTBD). Here, we comprehensively analyzed the assembly structure of MTCL1 to elucidate the molecular basis of this dual activity in microtubule regulation. Our results indicate that MTCL1 forms a parallel dimer not only through multiple homo-interactions of the central coiled-coil motifs, but also the most C-terminal non-coiled-coil region immediately downstream of the C-MTBD. Among these homo-interaction regions, the first coiled-coil motif adjacent to N-MTBD is sufficient for the MTCL1 function to crosslink microtubules without affecting the dynamic property, and disruption of this motif drastically transformed MTCL1-induced microtubule assembly from tight to network-like bundles. Notably, suppression of the homo-interaction of this motif inhibited the endogenous MTCL1 function to stabilize Golgi-associated microtubules that are essential for Golgi-ribbon formation. Because the microtubule-stabilizing activity of MTCL1 is completely attributed to C-MTBD, the present study suggests possible interplay between N-MTBD and C-MTBD, in which normal crosslinking and accumulation of microtubules by N-MTBD is essential for microtubule stabilization by C-MTBD.

Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel β4 subunit explain its role in cell–cell adhesion

Voltage-gated sodium channels (VGSCs) are transmembrane proteins required for the generation of action potentials in excitable cells and essential for propagating electrical impulses along nerve cells. VGSCs are complexes of a pore-forming α subunit and auxiliary β subunits, designated as β1/β1B–β4 (encoded by SCN1B–4B, respectively), which also function in cell–cell adhesion. We previously reported the structural basis for the trans homophilic interaction of the β4 subunit, which contributes to its adhesive function. Here, using crystallographic and biochemical analyses, we show that the β4 extracellular domains directly interact with each other in a parallel manner that involves an intermolecular disulfide bond between the unpaired Cys residues (Cys58) in the loop connecting strands B and C and intermolecular hydrophobic and hydrogen-bonding interactions of the N-terminal segments (Ser30-Val35). Under reducing conditions, an N-terminally deleted β4 mutant exhibited decreased cell adhesion compared with the wild type, indicating that the β4 cis dimer contributes to the trans homophilic interaction of β4 in cell–cell adhesion. Furthermore, this mutant exhibited increased association with the α subunit, indicating that the cis dimerization of β4 affects α–β4 complex formation. These observations provide the structural basis for the parallel dimer formation of β4 in VGSCs and reveal its mechanism in cell–cell adhesion.

POTENTIAL OF MEAN FORCE STUDY ON THE DIMERIZATION OF NON-AMYLOID-Β COMPONENT OF HUMAN Α-SYNUCLEIN

Self-association of α-Synuclein monomers into oligomeric species and highly ordered amyloid fibrils is linked to Parkinson’s disease (PD). The peptide fragment corresponding to region 61-95 of α-synuclein protein originally termed as non-amyloid β component (NAC) has been suggested to play a critical role in the fibrillation process. To better understand the early events of aggregation process, inter-molecular interactions between the two NAC regions during the formation of dimer is critical. Here we demonstrate the molecular dynamics and potential of mean force (PMF) techniques to study the parallel and anti-parallel dimers of the peptide corresponding to the 71-82 ( 71 VTGVTAVAQKTV 82 ) region of α-synuclein. From the PMF study, we noticed two basins of attraction, one at 10 Ǻ and 14 Ǻ for the parallel and only one basin near 12 Ǻ for the anti-parallel conformation of the dimer of the peptide. From docking study using SymmDock, we noticed higher side chain interactions and interface surface area for the anti-parallel conformation of the dimer of the peptide. Our results thus provide atomistic insights into the structural features of the core fibril forming NAC region during dimerization which may open the way to explore the molecular basis of this disease.

The IQGAP1 N-Terminus Forms Dimers, and the Dimer Interface Is Required for Binding F-Actin and Calcium-Bound Calmodulin.

IQGAP1 is a multidomain scaffold protein involved in many cellular processes. We have determined the crystal structure of an N-terminal fragment spanning residues 1-191 (CHDF hereafter) that contains the entire calponin homology domain. The structure of the CHDF is very similar to those of other type 3 calponin homology domains like those from calponin, Vav, and the yeast IQGAP1 ortholog Rng2. However, in the crystal, two CHDF molecules form a "head-to-head" or parallel dimer through mostly hydrophobic interactions. Binding experiments indicate that the CHDF binds to both F-actin and Ca2+/calmodulin, but binding is mutually exclusive. On the basis of the structure, two dimer interface substitutions were introduced. While CHDFL157D disrupts the dimer in gel filtration experiments, oxidized CHDFK161C stabilizes the dimer. These results imply that the CHDF forms the same dimer in solution that is seen in the crystal structure. The disulfide-stabilized dimer displays a reduced level of F-actin binding in sedimentation assays and shows no binding to Ca2+/calmodulin in isothermal titration calorimetry (ITC) experiments, indicating that interface residues are utilized for both binding events. The Calmodulin Target Database predicts that residues 93KK94 are important for CaM binding, and indeed, the 93EE94 double mutation displays a reduced level of binding to Ca2+/calmodulin in ITC experiments. Our results indicate that the CHDF dimer interface is used for both F-actin and Ca2+/calmodulin binding, and the 93KK94 pair, near the interface, is also used for Ca2+/calmodulin binding. These results are also consistent with full-length IQGAP1 forming a parallel homodimer.

N-terminal Prion Protein Peptides (PrP(120–144)) Form Parallel In-register β-Sheets via Multiple Nucleation-dependent Pathways

The prion diseases are a family of fatal neurodegenerative diseases associated with the misfolding and accumulation of normal prion protein (PrPC) into its pathogenic scrapie form (PrPSc). Understanding the fundamentals of prion protein aggregation and the molecular architecture of PrPSc is key to unraveling the pathology of prion diseases. Our work investigates the early-stage aggregation of three prion protein peptides, corresponding to residues 120-144 of human (Hu), bank vole (BV), and Syrian hamster (SHa) prion protein, from disordered monomers to β-sheet-rich fibrillar structures. Using 12 μs discontinuous molecular dynamics simulations combined with the PRIME20 force field, we find that the Hu-, BV-, and SHaPrP(120-144) aggregate via multiple nucleation-dependent pathways to form U-shaped, S-shaped, and Ω-shaped protofilaments. The S-shaped HuPrP(120-144) protofilament is similar to the amyloid core structure of HuPrP(112-141) predicted by Zweckstetter. HuPrP(120-144) has a shorter aggregation lag phase than BVPrP(120-144) followed by SHaPrP(120-144), consistent with experimental findings. Two amino acid substitutions I138M and I139M retard the formation of parallel in-register β-sheet dimers during the nucleation stage by increasing side chain-side chain association and reducing side chain interaction specificity. On average, HuPrP(120-144) aggregates contain more parallel β-sheet content than those formed by BV- and SHaPrP(120-144). Deletion of the C-terminal residues 138-144 prevents formation of fibrillar structures in agreement with the experiment. This work sheds light on the amyloid core structures underlying prion strains and how I138M, I139M, and S143N affect prion protein aggregation kinetics.

The Crystal Structures of the N-terminal Photosensory Core Module of Agrobacterium Phytochrome Agp1 as Parallel and Anti-parallel Dimers

Agp1 is a canonical biliverdin-binding bacteriophytochrome from the soil bacterium Agrobacterium fabrum that acts as a light-regulated histidine kinase. Crystal structures of the photosensory core modules (PCMs) of homologous phytochromes have provided a consistent picture of the structural changes that these proteins undergo during photoconversion between the parent red light-absorbing state (Pr) and the far-red light-absorbing state (Pfr). These changes include secondary structure rearrangements in the so-called tongue of the phytochrome-specific (PHY) domain and structural rearrangements within the long α-helix that connects the cGMP-specific phosphodiesterase, adenylyl cyclase, and FhlA (GAF) and the PHY domains. We present the crystal structures of the PCM of Agp1 at 2.70 Å resolution and of a surface-engineered mutant of this PCM at 1.85 Å resolution in the dark-adapted Pr states. Whereas in the mutant structure the dimer subunits are in anti-parallel orientation, the wild-type structure contains parallel subunits. The relative orientations between the PAS-GAF bidomain and the PHY domain are different in the two structures, due to movement involving two hinge regions in the GAF-PHY connecting α-helix and the tongue, indicating pronounced structural flexibility that may give rise to a dynamic Pr state. The resolution of the mutant structure enabled us to detect a sterically strained conformation of the chromophore at ring A that we attribute to the tight interaction with Pro-461 of the conserved PRXSF motif in the tongue. Based on this observation and on data from mutants where residues in the tongue region were replaced by alanine, we discuss the crucial roles of those residues in Pr-to-Pfr photoconversion.

The Structural Basis for Cdc42-Induced Dimerization of IQGAPs

In signaling, Rho-family GTPases bind effector proteins and alter their behavior. Here we present the crystal structure of Cdc42·GTP bound to the GTPase-activating protein (GAP)-related domain (GRD) of IQGAP2. Four molecules of Cdc42 are bound to two GRD molecules, which bind each other in a parallel dimer. Two Cdc42s bind very similarly to the Ras/RasGAP interaction, while the other two bind primarily to "extra domain" sequences from both GRDs, tying the GRDs together. Calorimetry confirms two-site binding of Cdc42·GTP for the GRDs of both IQGAP2 and IQGAP1. Mutation of important extra domain residues reduces binding to single-site and abrogates Cdc42 binding to a much larger IQGAP1 fragment. Importantly, Rac1·GTP displays only single-site binding to the GRDs, indicating that only Cdc42 promotes IQGAP dimerization. The structure identifies an unexpected role for Cdc42 in protein dimerization, thus expanding the repertoire of interactions of Ras family proteins with their targets.

The immunity-related GTPase Irga6 dimerizes in a parallel head-to-head fashion.

BackgroundThe immunity-related GTPases (IRGs) constitute a powerful cell-autonomous resistance system against several intracellular pathogens. Irga6 is a dynamin-like protein that oligomerizes at the parasitophorous vacuolar membrane (PVM) of Toxoplasma gondii leading to its vesiculation. Based on a previous biochemical analysis, it has been proposed that the GTPase domains of Irga6 dimerize in an antiparallel fashion during oligomerization.ResultsWe determined the crystal structure of an oligomerization-impaired Irga6 mutant bound to a non-hydrolyzable GTP analog. Contrary to the previous model, the structure shows that the GTPase domains dimerize in a parallel fashion. The nucleotides in the center of the interface participate in dimerization by forming symmetric contacts with each other and with the switch I region of the opposing Irga6 molecule. The latter contact appears to activate GTP hydrolysis by stabilizing the position of the catalytic glutamate 106 in switch I close to the active site. Further dimerization contacts involve switch II, the G4 helix and the trans stabilizing loop.ConclusionsThe Irga6 structure features a parallel GTPase domain dimer, which appears to be a unifying feature of all dynamin and septin superfamily members. This study contributes important insights into the assembly and catalytic mechanisms of IRG proteins as prerequisite to understand their anti-microbial action.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0236-7) contains supplementary material, which is available to authorized users.

Regulation of PKR by RNA: Formation of Active and Inactive Dimers

PKR is a member of the eIF2α family of protein kinases that inhibit translational initiation in response to stress stimuli and functions as a key mediator of the interferon-induced antiviral response. PKR contains a dsRNA binding domain that bind to duplex regions present in viral RNAs, resulting in kinase activation and autophosphorylation. An emerging theme in the regulation of protein kinases is the allosteric linkage of dimerization and activation. The PKR kinase domain forms a back-to-back parallel dimer which is implicated in activation. We have developed a sensitive homo-FRET assay for kinase domain dimerization to directly probe the relationship between RNA binding, activation, and dimerization. In the case of perfect duplex RNAs, dimerization is correlated with activation and dsRNAs containing 30 bp or more efficiently induce kinase domain dimerization and activation. However, more complex duplex RNAs containing a 10-15 bp 2'-O-methyl RNA barrier produce kinase dimers but do not activate. Similarly, inactivating mutations within the PKR dimer interface that disrupt key electrostatic and hydrogen binding interactions fail to abolish dimerization. Our data support a model where activating RNAs induce formation of a back-to-back parallel PKR kinase dimer whereas nonactivating RNAs either fail to induce dimerization or produce an alternative, inactive dimer configuration, providing an additional mechanism for distinguishing between host and pathogen RNA.

Heterodimerization of Neuropilin-1 Transmembrane Helices and Plexin Signaling

Heterodimerization of transmembrane helices of cell surface receptors is emerging as an important theme in cellular signaling. The most common motif for dimerization of alpha-helical transmembrane proteins is the GXXG motif. Neuropilin-1 (Nrp1) and Plexin D1 (Pld1) are both single-pass transmembrane receptors expressed in all vertebrate systems. The ligands for Nrp1 and Pld1 are a class of guidance molecules called Semaphorin 3 (Sema3). Signaling by all Sema3 ligands (except Sema3E) through Pld1 requires Nrp1. The Sema3/Nrp1/Pld1 signaling axis plays a role in angiogenesis, immune responses, cancer metastasis as well as invasiveness. Despite the established roles in normal physiology and pathology, the molecular details of signaling pathways involved are not well documented. There are no structural/mechanistic level details; it is still unknown which domain/domains of Nrp1 and Pld1 interact. Here we report heterodimerization of the transmembrane (TM) helices of Nrp1 and Pld1. Nrp1 has two GXXG motifs and it is established that the dimerization of the Nrp1 TM helices is important for signaling. Using NMR and all-atom molecular dynamics simulations we show that Nrp1 and Pld1 forms a parallel transmembrane helix dimer. Further, we compare this heterodimer with Nrp1 homodimer and show that the homodimer utilizes the C-terminal GXXG motif of Nrp1 for dimerization. Whereas, the Nrp1/Pld1 heterodimer uses the N-terminal GXXG motif. The ability to use alternative surfaces for dimerization likely has implications for the higher-order assembly of Nrp1/Pld1 in the membrane. Further, using functional assays we show that the heterodimerization of Nrp1 TM helices is essential for Sema3/Nrp1/Pld1 signaling. This to our knowledge is the first report of a functional role for transmembrane helix dimerization in Plexin signaling.

Thermodynamics and kinetics of amphotericin B self-association in aqueous solution characterized in molecular detail.

Amphotericin B (AmB) is a potent but toxic drug commonly used to treat systemic mycoses. Its efficiency as a therapeutic agent depends on its ability to discriminate between mammalian and fungal cell membranes. The association of AmB monomers in an aqueous environment plays an important role in drug selectivity, as oligomers formed prior to membrane insertion – presumably dimers – are believed to act differently on fungal (ergosterol-rich) and mammalian (cholesterol-rich) membranes. In this work, we investigate the initial steps of AmB self-association by studying the structural, thermodynamic and spectral properties of AmB dimers in aqueous medium using molecular dynamics simulations. Our results show that in water, the hydrophobic aggregation of AmB monomers yields almost equiprobable populations of parallel and antiparallel dimers that rapidly interconvert into each other, and the dipole-dipole interaction between zwitterionic head groups plays a minor role in determining the drug’s tendency for self-aggregation. A simulation of circular dichroism (CD) spectra indicates that in experimental measurements, the signature CD spectrum of AmB aggregates should be attributed to higher-order oligomers rather than dimers. Finally, we suggest that oligomerization can impair the selectivity of AmB molecules for fungal membranes by increasing their hydrophobic drive for non-specific membrane insertion.

Theoretical investigation of the substitution effects on carrier transport properties of tetrathia[22]annulene-[2,1,2,1] derivatives

The charge transport properties of tetrathia[22]annulene-[2,1,2,1] derivatives (DPTTA, $$\hbox {DPTTACH}_{3}$$ and DPTTACl) were investigated by the density functional theory coupled with incoherent charge-hopping model at the molecular and crystal levels to shed light on the relationship between the charger carrier mobility and substitution effects. It is found that that the low-lying and delocalized LUMOs and larger adiabatic electron affinities of these compounds are beneficial to their stability when acting as n-type organic semiconductors. The reorganization energy and transfer integral can significantly influence the charge carrier mobility. The $$\hbox {DPTTACH}_{3}$$ has large electron mobility ( $$0.177\hbox { cm}^{2}\cdot \hbox { V}^{-1}\cdot \hbox { s}^{-1}$$ ) owing to the small reorganization energy and larger transfer integral originating from the face-to-face $$\uppi $$ – $$\uppi $$ stacking among the three compounds. From the viewpoint of transfer integral, the transfer integral among the dominant hopping pathways indicates that the charge transport occurs in the parallel dimers with $$\uppi $$ – $$\uppi $$ interaction. On the basis of the angular resolution anisotropic mobility investigation, the $$\hbox {DPTTACH}_{3}$$ exhibit remarkable anisotropic behavior. We hope that our work can help the experimenters understand how to tune charge transport through a small molecular modification.

Regulation of PKR by RNA: formation of active and inactive dimers.

PKR is a member of the eIF2α family of protein kinases that inhibit translational initiation in response to stress stimuli and functions as a key mediator of the interferon-induced antiviral response. PKR contains a dsRNA binding domain that binds to duplex regions present in viral RNAs, resulting in kinase activation and autophosphorylation. An emerging theme in the regulation of protein kinases is the allosteric linkage of dimerization and activation. The PKR kinase domain forms a back-to-back parallel dimer that is implicated in activation. We have developed a sensitive homo-Förster resonance energy transfer assay for kinase domain dimerization to directly probe the relationship among RNA binding, activation, and dimerization. In the case of perfect duplex RNAs, dimerization is correlated with activation and dsRNAs containing 30 bp or more efficiently induce kinase domain dimerization and activation. However, more complex duplex RNAs containing a 10-15 bp 2'-O-methyl RNA barrier produce kinase dimers but do not activate. Similarly, inactivating mutations within the PKR dimer interface that disrupt key electrostatic and hydrogen binding interactions fail to abolish dimerization. Our data support a model in which activating RNAs induce formation of a back-to-back parallel PKR kinase dimer whereas nonactivating RNAs either fail to induce dimerization or produce an alternative, inactive dimer configuration, providing an additional mechanism for distinguishing between host and pathogen RNA.

Analysis of distinct molecular assembly complexes of keratin K8 and K18 by hydrogen-deuterium exchange.

Keratins are intermediate filament (IF) proteins that form complex filament systems in epithelial cells, thus serving as scaffolding elements and mechanical stress absorbers. The building blocks of keratin IFs are parallel coiled-coil dimers of two distinct sequence-related proteins distinguished as type I and type II keratins. To gain more insight into their structural dynamics, we resorted to hydrogen-deuterium exchange mass spectrometry of keratins K8 and K18, which are characteristic for simple epithelial cells. Using this powerful technique not employed with IFs before, we mapped patterns of protected versus unprotected regions in keratin complexes at various assembly levels. In particular, we localized protein segments exhibiting different hydrogen exchange patterns in tetramers versus filaments. We observed a general pattern of precisely positioned regions of stability intertwining with flexible regions, mostly represented by the non-α-helical segments. Notably, some regions within the coiled-coil domains are significantly more dynamic than others, while the IF-consensus motifs at the end domains of the central α-helical "rod" segment, which mediate the "head-to-tail" dimer-dimer interaction in the filament elongation process, become distinctly more protected upon formation of filaments. Moreover, to gain more insight into the dynamics of the individual keratins, we investigated the properties of homomeric preparations of K8 and K18. The physiological importance of keratins without a partner is encountered in both pathological and experimental situations when one of the two species is present in robust excess or completely absent, such as in gene-targeted mice.

Oligomerization of Mumps Virus Phosphoprotein.

The mumps virus (MuV) genome encodes a phosphoprotein (P) that is important for viral RNA synthesis. P forms the viral RNA-dependent RNA polymerase with the large protein (L). P also interacts with the viral nucleoprotein (NP) and self-associates to form a homotetramer. The P protein consists of three domains, the N-terminal domain (P(N)), the oligomerization domain (P(O)), and the C-terminal domain (P(C)). While P(N) is known to relax the NP-bound RNA genome, the roles of P(O) and P(C) are not clear. In this study, we investigated the roles of P(O) and P(C) in viral RNA synthesis using mutational analysis and a minigenome system. We found that P(N) and P(C) functions can be trans-complemented. However, this complementation requires P(O), indicating that P(O) is essential for P function. Using this trans-complementation system, we found that P forms parallel dimers (P(N) to P(N) and P(C) to P(C)). Furthermore, we found that residues R231, K238, K253, and K260 in P(O) are critical for P's functions. We identified P(C) to be the domain that interacts with L. These results provide structure-function insights into the role of MuV P. MuV, a paramyxovirus, is an important human pathogen. The P protein of MuV is critical for viral RNA synthesis. In this work, we established a novel minigenome system that allows the domains of P to be complemented in trans. Using this system, we confirmed that MuV P forms parallel dimers. An understanding of viral RNA synthesis will allow the design of better vaccines and the development of antivirals.

Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain.

Receptor and nonreceptor tyrosine kinases are enzymes that play important roles in regulating signal transduction pathways in a variety of normal cellular process and in many pathological conditions. Ordered phosphorylation is required for receptor tyrosine kinase (RTK) activation, a process mediated by transient dimer formation of the kinase domains. This process is triggered by the tyrosine phosphorylation in the activation loop. Here, we report structural and biochemical analyses of the tyrosine kinase domain interaction of fibroblast growth factor receptor 1 (FGFR1) required for the initial phosphorylation step. On the basis of nuclear magnetic resonance (NMR) analysis and covalent cross-linking experiments, we propose a parallel symmetric dimer model where specific contacts are formed between the N-lobes and C-lobes, respectively, in the FGFR1 kinase domains. Moreover, assignment of the contact sites between two FGFR1 kinase domains are supported by a trans-phosphorylation assay and by mutational analyses. The present report shows the molecular mechanism underlying the control of trans-phosphorylation of a critical auto-regulatory site in FGF receptors' catalytic domain.

Computational investigation on tunable optical band gap in armchair polyacenes.

Polyacenes in their armchair geometry (phenacenes) have recently been found to possess appealing electronic and optical properties with higher chemical stability and comparatively larger band gap as compared to linear polyacenes. They also behave as high-temperature superconductors upon alkali metal doping. Moreover, the optical properties of crystalline picene can be finely tuned by applying external pressure. We investigated the variation of optical gap as a function of altering the interplanar distances between parallel cofacial phenacene dimers. We employed both time-dependent density functional theory and density matrix renormalization group (DMRG) technique to investigate the lowest singlet excitations in phenacene dimer. Our study showed that the lowest singlet excitation in these systems evolved as a function of interplanar separation. The optical excitation energy gap decreases as a function of inverse interplanar separation of the phenacene dimer. The distant dependent variation of optical absorption at the dimer level may be comparable with experimental observation in picene crystal under pressure. DMRG study also demonstrates that besides picene, electronic properties of higher phenacenes can also be tunable by altering interplanar separation.