S28 peptidases: lessons from a seemingly 'dysfunctional' family of two

<p>Abstract</p> <p>A recent paper in <it>BMC Structural Biology </it>reports the crystal structure of human prolylcarboxypeptidase (PRCP), one of the two members of the S28 peptidase family. Comparison of the substrate-binding site of PRCP with that of its family partner, dipeptidyl dipeptidase 7 (DPP7), helps to explain the different enzymatic activities of these structurally similar proteins, and also reveals a novel apparent charge-relay system in PRCP involving the active-site catalytic histidine.</p> <p>See research article: <url>http://www.biomedcentral.com/1472-6807/10/16/</url></p> <p>Commentary</p> <p>The S28 serine peptidase family is something of an enzymatic odd couple. While showing low sequence similarity to all proteins except each other, the two known family members appear to be at odds functionally; one, prolylcarboxypeptidase (PRCP), is a carboxypeptidase that cleaves single hydrophobic residues from the carboxyl termini of proteins that end with a Pro-X motif (where X is any hydrophobic amino acid), while the other, human dipeptidyl peptidase (DPP7), is an aminopeptidase that cleaves amino-terminal X-Pro dipeptides. The structural basis of this orthogonal specificity would undoubtedly be interesting, and a recent report in <it>BMC Structural Biology </it>from the Merck Global Structural Biology group (Soisson <it>et al</it>. <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>) has now met that expectation. In addition they reveal a new wrinkle to the iconic catalytic triad common to most serine hydrolases.</p> <p>The practical pharmaceutical interest in both these enzymes as potential drug targets is at present speculative. PRCP can inactivate a number of peptide hormones, such as angiotensin II, III and prekallikrein, implicating a role for the enzyme in hypertension, tissue proliferation and smooth-muscle growth. These properties suggest that this enzyme may well be a useful target for hypertension and anti-inflammatory therapy <abbrgrp><abbr bid="B2">2</abbr></abbrgrp>. Another (non-S28 family) dipeptidyl dipeptidase (DPP4) is a major drug target in type 2 diabetes, and Merck has already developed a successful inhibitor of DPP4, the anti-hyperglycemic drug sitagliptin, for the treatment of type 2 diabetes. The DPP enzymes are rich in biological functions and other drug targets emerging from the group are possible <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>.</p

A natural Finsler--Laplace operator

We give a new definition of a Laplace operator for Finsler metric as an average with regard to an angle measure of the second directional derivatives. This definition uses a dynamical approach due to Foulon that does not require the use of connections nor local coordinates. We show using 1-parameter families of Katok--Ziller metrics that this Finsler--Laplace operator admits explicit representations and computations of spectral data.Comment: 25 pages, v2: minor modifications, changed the introductio

ρ\rho-Meson Production and Decay in Proton-Nucleus Collisions

We analyze the production of $\rho$-mesons in $p + A$ reactions including both the production by proton-nucleon as well as pion-nucleon collisions within a coupled channel transport approach. The final state interactions of the $\rho$-meson with nucleons are evaluated from a resonance model which allows to extract elastic and inelastic cross sections. We include the latter final state interactions, the $\rho$-meson decay into two pions as well as the final pion-nucleon interactions within the transport approach. We find the invariant mass distribution of pion pairs to be sensitive to the $\rho$-meson properties in the nuclear medium. However, due to the strong final state interactions of pions only light targets like $^{12}C$ might be suited to extract a $\rho$-signal from the uncorrelated two pion background which carries information about the in-medium properties of the $\rho$-meson.Comment: 27 pages, LaTeX, including 13 ps-figures, UGI-97-20, Nucl. Phys. A., in pres

RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions

Loneliness, social support and cardiovascular reactivity to laboratory stress

Self-reported or explicit loneliness and social support have been inconsistently associated with cardiovascular reactivity (CVR) to stress. The present study aimed to adapt an implicit measure of loneliness, and use it alongside the measures of explicit loneliness and social support, to investigate their correlations with CVR to laboratory stress. Twenty-five female volunteers aged between 18 and 39 years completed self-reported measures of loneliness and social support, and an Implicit Association Test (IAT) of loneliness. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) reactivity indices were measured in response to psychosocial stress induced in the laboratory. Functional support indices of social support were significantly correlated with CVR reactivity to stress. Interestingly, implicit, but not explicit, loneliness was significantly correlated with DBP reactivity after one of the stressors. No associations were found between structural support and CVR indices. Results are discussed in terms of validity of implicit versus explicit measures and possible factors that affect physiological outcomes

Dose-response relationship between ambulatory load magnitude and load-induced changes in COMP in young healthy adults

To determine the dose-response relationship between ambulatory load magnitude during a walking stress test and load-induced changes in serum concentration of cartilage oligomeric matrix protein (sCOMP) in healthy subjects.; sCOMP was assessed before and after a 30-min walking stress test performed on three test days by 24 healthy volunteers. In each walking stress test, one of three ambulatory loads was applied in a block randomized crossover design: normal body weight (BW) (100%BW = normal load); reduced BW (80%BW = reduced load); increased BW (120%BW = increased load). Knee kinematics and ground reaction force (GRF) were measured using an inertial sensor gait analysis system and a pressure plate embedded in the treadmill.; Load-induced increases in sCOMP rose with increasing ambulatory load magnitude. Mean sCOMP levels increased immediately after the walking stress test by 26.8 ± 12.8%, 28.0 ± 13.3% and 37.3 ± 18.3% for the reduced, normal or increased load condition, respectively. Lower extremity kinematics did not differ between conditions.; The results of this study provide important evidence of a dose-response relationship between ambulatory load magnitude and load-induced changes in sCOMP. Our data suggests that in normal weight persons sCOMP levels are more sensitive to increased than to reduced load. The experimental framework presented here may form the basis for studying the relevance of the dose-response relationship between ambulatory load magnitude and load-induced changes in biomarkers involved in metabolism of healthy articular cartilage and after injury

A mechanism for the Double-Spin Asymmetry in Electromagnetic ρ\rho Production at HERMES

We calculate the contribution of meson and pomeron exchanges to the double-spin asymmetry in $\rho$-meson electromagnetic production at HERMES energies. We show that the observed double-spin asymmetries, which are large, can be explained by the interference between the natural parity $f_2$-secondary Reggeon and the unnatural parity anomalous $f_1$ exchanges.Comment: 7 pages, 3 figures, Late

Exclusive diffractive processes and the quark substructure of mesons

Exclusive diffractive processes on the nucleon are investigated within a model in which the quark-nucleon interaction is mediated by Pomeron exchange and the quark substructure of mesons is described within a framework based on the Dyson-Schwinger equations of QCD. The model quark-nucleon interaction has four parameters which are completely determined by high-energy $\pi N$ and $K N$ elastic scattering data. The model is then used to predict vector-meson electroproduction observables. The obtained $\rho$- and $\phi$-meson electroproduction cross sections are in excellent agreement with experimental data. The predicted $q^2$ dependence of $J/\psi$-meson electroproduction also agrees with experimental data. It is shown that confined-quark dynamics play a central role in determining the behavior of the diffractive, vector-meson electroproduction cross section. In particular, the onset of the asymptotic $1/q^4$ behavior of the cross section is determined by a momentum scale that is set by the current-quark masses of the quark and antiquark inside the vector meson. This is the origin of the striking differences between the $q^2$ dependence of $\rho$-, $\phi$- and $J/\psi$-meson electroproduction cross sections observed in recent experiments.Comment: 53 pages, 23 figures, revtex and epsfig. Minor additions to tex

Architecture of North Atlantic contourite drifts modified by transient circulation of the Icelandic mantle plume

Overflow of Northern Component Water, the precursor of North Atlantic Deep Water, appears to have varied during Neogene times. It has been suggested that this variation is moderated by transient behavior of the Icelandic mantle plume, which has influenced North Atlantic bathymetry through time. Thus pathways and intensities of bottom currents that control deposition of contourite drifts could be affected by mantle processes. Here, we present regional seismic reflection profiles that cross sedimentary accumulations (Björn, Gardar, Eirik and Hatton Drifts). Prominent reflections were mapped and calibrated using a combination of boreholes and legacy seismic profiles. Interpreted seismic profiles were used to reconstruct solid sedimentation rates. Björn Drift began to accumulate in late Miocene times. Its average sedimentation rate decreased at ∼2.5 Ma and increased again at ∼0.75 Ma. In contrast, Eirik Drift started to accumulate in early Miocene times. Its average sedimentation rate increased at ∼5.5 Ma and decreased at ∼2.2 Ma. In both cases, there is a good correlation between sedimentation rates, inferred Northern Component Water overflow, and the variation of Icelandic plume temperature independently obtained from the geometry of diachronous V-shaped ridges. Between 5.5 and 2.5 Ma, the plume cooled, which probably caused subsidence of the Greenland-Iceland-Scotland Ridge, allowing drift accumulation to increase. When the plume became hotter at 2.5 Ma, drift accumulation rate fell. We infer that deep-water current strength is modulated by fluctuating dynamic support of the Greenland-Scotland Ridge. Our results highlight the potential link between mantle convective processes and ocean circulationThis work is partly supported by Natural Environment Research Council Grant NE/G007632/1. RPT was supported by the University of Cambridge Girdler Fund and by BP Exploration.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/2015GC00594