Regulating the human HECT E3 ligases

Ubiquitination, the covalent attachment of ubiquitin to proteins, by E3 ligases of the HECT (homologous to E6AP C terminus) family is critical in controlling diverse physiological pathways. Stringent control of HECT E3 ligase activity and substrate specificity is essential for cellular health, whereas deregulation of HECT E3s plays a prominent role in disease. The cell employs a wide variety of regulatory mechanisms to control HECT E3 activity and substrate specificity. Here, we summarize the current understanding of these regulatory mechanisms that control HECT E3 function. Substrate specificity is generally determined by interactions of adaptor proteins with domains in the N-terminal extensions of HECT E3 ligases. These N-terminal domains have also been found to interact with the HECT domain, resulting in the formation of inhibitory conformations. In addition, catalytic activity of the HECT domain is commonly regulated at the level of E2 recruitment and through HECT E3 oligomerization. The previously mentioned regulatory mechanisms can be controlled through protein–protein interactions, post-translational modifications, the binding of calcium ions, and more. Functional activity is determined not only by substrate recruitment and catalytic activity, but also by the type of ubiquitin polymers catalyzed to the substrate. While this is often determined by the specific HECT member, recent studies demonstrate that HECT E3s can be modulated to alter the type of ubiquitin polymers they catalyze. Insight into these diverse regulatory mechanisms that control HECT E3 activity may open up new avenues for therapeutic strategies aimed at inhibition or enhancement of HECT E3 function in disease-related pathways

A new formulation of Kapila\xe2\x80\x99s five-equation model for compressible two-fluid flow, and its numerical treatment

A new formulation of Kapila’s five-equation model for inviscid, non-heat-conducting, compressible two-fluid flow is derived, together with an appropriate numerical method. The new formulation uses flow equations based on conservation laws and exchange laws only. The two fluids exchange momentum and energy, for which exchange terms are derived from physical laws. All equations are written as a single system of equations in integral form. No equation is used to describe the topology of the two-fluid flow. Relations for the Riemann invariants of the governing equations are derived, and used in the construction of an Osher-type approximate Riemann solver. A consistent finite-volume discretization of the exchange terms is proposed. The exchange terms have distinct contributions in the cell interior and at the cell faces. For the exchange-term evaluation at the cell faces, the same Riemann solver as used for the flux evaluation is exploited. Numerical results are presented for two-fluid shock-tube and shock-bubble-interaction problems, the former also for a two-fluid mixture case. All results show good resemblance with reference results

Superconductivity in the New Platinum Germanides MPt4Ge12 (M = Rare-earth and Alkaline-earth Metals) with Filled Skutterudite Structure

New germanium-platinum compounds with the filled-skutterudite crystal structure were synthesized. The structure and composition were investigated by X-ray diffraction and microprobe analysis. Magnetic susceptibility, specific heat, and electrical resistivity measurements evidence superconductivity in LaPt4Ge12 and PrPt4Ge12 below 8.3K. The parameters of the normal and superconducting states were established. Strong coupling and a crystal electric field singlet groundstate is found for the Pr compound. Electronic structure calculations show a large density of states at the Fermi level. Similar behavior with lower T_c was observed for SrPt4Ge12 and BaPt4Ge12.Comment: RevTeX, 4 figures, submitted to Physical Review Letters July 12, 200

Roughness correction to the Casimir force at short separations: Contact distance and extreme value statistics

So far there has been no reliable method to calculate the Casimir force at separations comparable to the root-mean-square of the height fluctuations of the surfaces. Statistical analysis of rough gold samples has revealed the presence of peaks considerably higher than the root-mean-square roughness. These peaks redefine the minimum separation distance between the bodies and can be described by extreme value statistics. Here we show that the contribution of the high peaks to the Casimir force can be calculated with a pairwise additive summation, while the contribution of asperities with normal height can be evaluated perturbatively. This method provides a reliable estimate of the Casimir force at short distances, and it solves the significant, so far unexplained discrepancy between measurements of the Casimir force between rough surfaces and the results of perturbation theory. Furthermore, we illustrate the importance of our results in a technologically relevant situation.Comment: 29 pages, 11 figures, to appear in Phys. Rev.

Slipins: ancient origin, duplication and diversification of the stomatin protein family

<p>Abstract</p> <p>Background</p> <p>Stomatin is a membrane protein that was first isolated from human red blood cells. Since then, a number of stomatin-like proteins have been identified in all three domains of life. The conservation among these proteins is remarkable, with bacterial and human homologs sharing 50 % identity. Despite being associated with a variety of diseases such as cancer, kidney failure and anaemia, precise functions of these proteins remain unclear.</p> <p>Results</p> <p>We have constructed a comprehensive phylogeny of all 'stomatin-like' sequences that share a 150 amino acid domain. We show these proteins comprise an ancient family that arose early in prokaryotic evolution, and we propose a new nomenclature that reflects their phylogeny, based on the name "slipin" (stomatin-like protein). Within prokaryotes there are two distinct subfamilies that account for the two different origins of the eight eukaryotic stomatin subfamilies, one of which gave rise to eukaryotic SLP-2, renamed here "paraslipin". This was apparently acquired through the mitochondrial endosymbiosis and is widely distributed amongst the major kingdoms. The other prokaryotic subfamily gave rise to the ancestor of the remaining seven eukaryotic subfamilies. The highly diverged "alloslipin" subfamily is represented only by fungal, viral and ciliate sequences. The remaining six subfamilies, collectively termed "slipins", are confined to metazoa. Protostome stomatin, as well as a newly reported arthropod subfamily slipin-4, are restricted to invertebrate groups, whilst slipin-1 (previously SLP-1) is present in nematodes and higher metazoa. In vertebrates, the stomatin family expanded considerably, with at least two duplication events giving rise to podocin and slipin-3 subfamilies (previously SLP-3), with the retained ancestral sequence giving rise to vertebrate stomatin.</p> <p>Conclusion</p> <p>Stomatin-like proteins have their origin in an ancient duplication event that occurred early on in the evolution of prokaryotes. By constructing a phylogeny of this family, we have identified and named a number of orthologous groups: these can now be used to infer function of stomatin subfamilies in a meaningful way.</p

Experimental methods to assess the impact of climate change on plankton -Winter School on Impact of Climate Change on Indian Marine Fisheries held at CMFRI, Cochin 18.1.2008 to 7.2.2008

The influences of solar radiation and several components of the climate in an environment on the energy budgets in marine organisms are important in evaluating the biological productivity in aquatic systems. The flow of energy within the ecosystem is chiefly regulated at the level of primary and secondary production and the success of a biologically active marine ecosystem is defined by the richness of its community of primary and secondary producers. Temperature is perhaps the most important limiting factor determining the growth and biological activity of marine flora and fauna. The general processes in the ecosystem at a natural temperature may be obtained only if the temperature dependence of organisms is known. A few vantage groups of native flora and fauna, which can possibly be indicators of climate change, are usually selected for laboratory-based studies to demonstrate the effects of climate change on the organisms and the ecosystem