Protein arginine deiminase 4 (PAD4) is a transcriptional coregulator that catalyzes the calciumdependent conversion of specific arginine residues in proteins to citrulline.

We first give an overview of the shell-correction method which was developed by V. M.Strutinsky as a practicable and efficient approximation to the general selfconsistent theory of finite fermion systems suggested by A. B. Migdal and collaborators. Then we present in more detail a semiclassical theory of shell effects, also developed by Strutinsky following original ideas of M. Gutzwiller. We emphasize, in particular, the influence of orbit bifurcations on shell structure. We first give a short overview of semiclassical trace formulae, which connect the shell oscillations of a quantum system with a sum over periodic orbits of the corresponding classical system, in what is usually called the "periodic orbit theory". We then present a case study in which the gross features of a typical double-humped nuclear fission barrier, including the effects of mass asymmetry, can be obtained in terms of the shortest periodic orbits of a cavity model with realistic deformations relevant for nuclear fission. Next we investigate shell structures in a spheroidal cavity model which is integrable and allows for fargoing analytical computation. We show, in particular, how period-doubling bifurcations are closely connected to the existence of the so-called "superdeformed" energy minimum which corresponds to the fission isomer of actinide nuclei. Finally, we present a general class of radial power-law potentials which approximate well the shape of a Woods-Saxon potential in the bound region, give analytical trace formulae for it and discuss various limits (including the harmonic oscillator and the spherical box potentials).

Histone arginine methylation is a posttranslational modification linked to the regulation of gene transcription. Unlike other posttranslational modifications, methylation has generally been regarded as stable, and enzymes that demethylate histone arginine residues have not been identified. However, it has recently been shown that human peptidylarginine deiminase 4 (PAD4), a Ca 2؉ -dependent enzyme previously known to convert arginine residues to citrulline in histones, can also convert monomethylated arginine residues to citrulline both in vivo and in vitro. Citrullination of histone arginine residues by the enzyme antagonizes methylation by histone arginine methyltransferases and is thus a novel posttranslational modification that regulates the level of histone arginine methylation and gene activity. Here we present the crystal structures of a Ca 2؉ -bound PAD4 mutant in complex with three histone N-terminal peptides, each consisting of 10 amino acid residues that include one target arginine residue for the enzyme (H3͞Arg-8, H3͞Arg-17, and H4͞Arg-3). To each histone N-terminal peptide, the enzyme induces a ␤-turn-like bent conformation composed of five successive residues at the molecular surface near the active site cleft. The remaining five residues are highly disordered. The enzyme recognizes each peptide through backbone atoms of the peptide with a possible consensus recognition motif. The sequence specificity of the peptide recognized by this enzyme is thought to be fairly broad. These observations provide structural insights into target protein recognition by histone modification enzymes and illustrate how PAD4 can target multiple arginine sites in the histone N-terminal tails.calcium binding ͉ histone modification ͉ rheumatoid arthritis ͉ protein deimination͞citrullination ͉ x-ray crystal structure

The analytical trace formula for a dense cascade of bifurcations was derived using the improved stationary phase method based on extensions of the semiclassical Gutzwiller path integral approach. For the integrable version of the famous Hénon-Heiles Hamiltonian, our analytical trace formula solves all bifurcation problems, in particular, in the harmonic oscillator limit and the potential barrier limit. We obtain nice agreement with quantum results for gross to finer shell structures in level densities and for the shell structure energies, even near the potential barrier where there is a rather dense sequence of bifurcations. §1. IntroductionThe Gutzwiller trace formula 1), 2) and its extensions to continuous symmetries 3)-9) are nice tools to study shell structures in finite fermionic systems. This is the socalled periodic orbit theory (POT), which relates quantum fluctuations in singleparticle level densities to classical periodic orbits through their dynamical characteristics, such as action integrals, stability matrices, and degeneracy (symmetry) parameters.Recently, the POT was employed in studies seeking to overcome some symmetrybreaking problems related to divergencies and discontinuities of the standard stationary phase method (standard SPM, SSPM) 2), 9) due to a bifurcation phenomenon. For instance, the improved stationary phase method (ISPM) within the extended Gutzwiller approach (EGA) 10)-12) was used in derivations of the trace formulas. The ISPM is based on the theory of critical caustics and turning points formulated by Maslov and Fedoryuk 13)-17) in order to overcome bifurcation problems. Furthermore, the idea of Berry and Tabor 5) has been applied to calculate catastrophe integrals more exactly within finite limits over the accessible phase space volume for classical motion.Other semiclassical approaches, known as the uniform approximations, were suggested and successfully developed previously 18)-26) on the basis of the theory of

We derive a semiclassical trace formula for the level density of the three-dimensional spheroidal cavity. To overcome the divergences and discontinuities occurring at bifurcation points and in the spherical limit, the trace integrals over the action-angle variables are performed using an improved stationary phase method. The resulting semiclassical level density oscillations and shell energies are in good agreement with quantum-mechanical results. We find that the births of three-dimensional orbits through the bifurcations of planar orbits in the equatorial plane lead to considerable enhancement of shell effect for superdeformed shapes. * ) In this paper SSPM denotes the standard stationary phase method and its extension to continuous symmetries. 3)-5), 7)

p62/SQSTM1/A170 is a multimodular protein that is found in ubiquitin-positive inclusions associated with neurodegenerative diseases. Recent findings indicate that p62 mediates the interaction between ubiquitinated proteins and autophagosomes, leading these proteins to be degraded via the autophagy-lysosomal pathway. This ubiquitin-mediated selective autophagy is thought to begin with recognition of the ubiquitinated proteins by the C-terminal ubiquitin-associated (UBA) domain of p62. We present here the crystal structure of the UBA domain of mouse p62 and the solution structure of its ubiquitin-bound form. The p62 UBA domain adopts a novel dimeric structure in crystals, which is distinctive from those of other UBA domains. NMR analyses reveal that in solution the domain exists in equilibrium between the dimer and monomer forms, and binding ubiquitin shifts the equilibrium toward the monomer to form a 1:1 complex between the UBA domain and ubiquitin. The dimer-to-monomer transition is associated with a structural change of the very C-terminal end of the p62 UBA domain, although the UBA fold itself is essentially maintained. Our data illustrate that dimerization and ubiquitin binding of the p62 UBA domain are incompatible with each other. These observations reveal an autoinhibitory mechanism in the p62 UBA domain and suggest that autoinhibition plays a role in the function of p62.Impairment of the ubiquitin-proteasome system is one of major causes of ubiquitin-positive inclusions found in various neurodegenerative diseases (1). Recent studies have identified the involvement of another degradation system, the autophagy-lysosomal pathway, in the formation of ubiquitin-positive inclusions as exemplified by the observation that autophagy-deficient mice exhibit substantial accumulation of such inclusions in tissues (2). p62/SQSTM1/A170, a multidomain protein found in ubiquitin-positive inclusions, has been shown to bind intracellular signaling factors (3-5). Accumulating evidence indicates that p62 is a receptor for ubiquitinated proteins that are targeted to the autophagosome for lysosomal degradation. Specifically, it is involved in autophagic elimination of damaged mitochondria, midbody rings, peroxisomes, and microbes (6 -10).The importance of p62 in autophagic degradation of proteins and organelles has been demonstrated by studies using tissuespecific autophagy-deficient mice. Elimination of Atg5 or Atg7, an essential gene in the formation of the autophagosome, in mouse neurons and hepatocytes resulted in toxicity accompanied by accumulation of ubiquitin-positive inclusions in the cells. In contrast, knock-out of both Atg7 and p62 (Atg7 Ϫ/Ϫ / p62 Ϫ/Ϫ ) caused a dramatic reduction in the amount of inclusions in both types of cells (2, 11). A similar result was also reported in fruit flies (12). These observations indicate that p62 is critically involved in the development of ubiquitin-positive inclusions that should be degraded via autophagy. In addition to playing a role in the autophagy-lysosomal pathway, p62 its...

We derive an analytical trace formula for the level density of two-dimensional elliptic billiards using an improved stationary phase method. The result is a continuous function of the deformation parameter (eccentricity) through all bifurcation points of the short diameter orbit and its repetitions, and possesses the correct limit of circular billiard at zero eccentricity. Away from the circular limit and the bifurcations, it reduces to the usual (extended) Gutzwiller trace formula, which for the leading-order families of periodic orbits is identical to the result of Berry and Tabor. We show that the circular disk limit of the diameter-orbit contribution is also reached through contributions from closed (periodic and non-periodic) orbits of the hyperbolic type with an even number of reflections from the boundary. We obtain the Maslov indices depending on deformation and energy in terms of the phases of the complex error and Airy functions. We find enhancement of the amplitudes near the common bifurcation points of short-diameter and hyperbolic orbits. The calculated semiclassical level densities and shell energies are in good agreement with the quantum mechanical ones. §1. IntroductionThe periodic orbit theory (POT), developed by Gutzwiller 1), 2) for chaotic systems, by Balian and Bloch 3) for cavities, and by Berry and Tabor 4), 5) for integrable systems, has proved to be an important semiclassical tool not only for an approximate quantization but also for the description of gross-shell effects in finite fermion systems. 6), 7) Gutzwiller's approach has been extended to take into account continuous symmetries 6), 8) -12) and is therefore applicable to systems with mixed classical dynamics, including the integrable and hard-chaos limits.An important role is played by the classical degeneracy of the periodic orbits in systems with continuous spatial or dynamical symmetries: the orbits are then not isolated in phase space (as assumed in Gutzwiller's original trace formula, and as is the case in chaotic systems), but occur in degenerate families with identical actions.

phosphatase which is distributed among eubacteria, archia and eukaryotes. In E. coli, it is necessary for survival during the stationary phase, but the physiological role of SurE is not clear. Crystal structures of SurE from Thermotoga maritima and Pyrobaculum aerophilum have been determined, which revealed that SurE forms a dimer that assembles into a tetramer.We report here the crystal structures of SurE from Thermus thermolhilus HB8 (SurE ther ) in a few different space groups. The SurE ther structure consists of a globular Rossmann fold domain and a protruded domain that mediates tetramerization as so far-reported structures. However, the angle between the protruding domain and the Rossmann fold domain of SurE ther is different. As a result, the dimeric-and tetrameric-structures of SurE ther were quite different from the known SurE structures. We studied the self-associative properties of SurE ther in solution using the sedimentation equilibrium analytical ultracentrifugation. Phosphatase activity assays of SurE ther is in progress, and its substrate specificity seems to be strict compared to SurE from other species. The relationship between enzymatic property and the variant oligomeric structure of SurE ther will be discussed. Galactosidase I from Mortierella vinacea ( -Gal I) consists of 397 amino acid residues and it shows high activity to increase the yield of sucrose by eliminating raffinose, which prevents normal crystallization of beet sugar, and is sometimes referred to as raffinase.-Gal I is considered to be a glycoprotein, resulting from the presence of its sugar chain. In addition, the gel filtration data shows that -Gal I might exist as a tetramer in solution.In order to understand the catalytic mechanism, we conducted structure analysis of this enzyme. Crystals of -Gal I were obtained by the hanging drop vapour diffusion method using the polyethylene glycol 400 as a precipitant. Diffraction experiments were conducted at the Photon Factory, and the data up to 1.6 Å resolution were collected. Structure was determined by the molecular replacement method and the final model gave a crystallographic R-factor of 0.133 and an R freefactor of 0.157. Owing to the high resolution X-ray data, four carbohydrate chains were observed in one -Gal I molecule and their structures were identified to be high mannose type. -Gal I seemed to form a tetramer around the crystallographic four-fold axis. Peptidylarginine deiminase 4 (PAD4) is a Ca 2+ -dependent enzyme that catalyzes the conversion of protein arginine residues to citrulline residues. PAD4 is expressed mainly in bloodstream granulocytes and present in the cell nucleus. The recent experimental evidence that PAD4 targets multiple arginine sites in histone H3 and H4, including those sites methylated by CARM1 (H3/Arg17) and PRMT1 (H4/Arg3), has attracted considerable attention to characterize the role of histone modifications in regulating gene transcription [1, 2].On the other hand, a recent single-nucleotide polymorphism (SNP) analysis of the PAD4 (PADI4) gen...