Structural Analysis of the UBA Domain of X-linked Inhibitor of Apoptosis Protein Reveals Different Surfaces for Ubiquitin-Binding and Self-Association

BACKGROUND: Inhibitor of apoptosis proteins (IAPs) belong to a pivotal antiapoptotic protein family that plays a crucial role in tumorigenesis, cancer progression, chemoresistance and poor patient-survival. X-linked inhibitor of apoptosis protein (XIAP) is a prominent member of IAPs attracting intense research because it has been demonstrated to be a physiological inhibitor of caspases and apoptosis. Recently, an evolutionarily conserved ubiquitin-associated (UBA) domain was identified in XIAP and a number of RING domain-bearing IAPs. This has placed the IAPs in the group of ubiquitin binding proteins. Here, we explore the three-dimensional structure of the XIAP UBA domain (XIAP-UBA) and how it interacts with mono-ubiquitin and diubiquitin conjugates. PRINCIPAL FINDINGS: The solution structure of the XIAP-UBA domain was determined by NMR spectroscopy. XIAP-UBA adopts a typical UBA domain fold of three tightly packed alpha-helices but with an additional N-terminal 3(10) helix. The XIAP-UBA binds mono-ubiquitin as well as Lys48-linked and linear-linked diubiquitins at low-micromolar affinities. NMR analysis of the XIAP-UBA-ubiquitin interaction reveals that it involves the classical hydrophobic patches surrounding Ile44 of ubiquitin and the conserved MGF/LV motif surfaces on XIAP-UBA. Furthermore, dimerization of XIAP-UBA was observed. Mapping of the self-association surface of XIAP-UBA reveals that the dimerization interface is formed by residues in the N-terminal 3(10) helix, helix alpha1 and helix alpha2, separate from the ubiquitin-binding surface. CONCLUSION: Our results provide the first structural information of XIAP-UBA and map its interaction with mono-ubiquitin, Lys48-linked and linear-linked diubiquitins. The notion that XIAP-UBA uses different surfaces for ubiquitin-binding and self-association provides a plausible model to explain the reported selectivity of XIAP in binding polyubiquitin chains with different linkages.published_or_final_versio

Allergy and Immunology

The main physiologic function of the immune system - protection of the host from infection for many years characterized the immune response in its ability to distinguish between “foreign” and “self”, the key issue being that foreign was to be attacked and eradicated, while self was not to be attacked. In recent years, however, from the wide range of diseases that are consequent to inappropriate immune functions, we have learned that the ability of the immune system to distinguish between harmful and harmless molecules or cells rather than characterizing the dichotomy as foreign and self is essential for mounting protective immune responses and preventing the induction of pathology

A taxonomy and results from a comprehensive review of 28 maternal health voucher programmes

It is increasingly clear that Millennium Development Goal 4 and 5 will not be achieved in many low- and middle-income countries with the weakest gains among the poor. Recognizing that there are large inequalities in reproductive health outcomes, the post-2015 agenda on universal health coverage will likely generate strategies that target resources where maternal and newborn deaths are the highest. In 2012, the United States Agency for International Development convened an Evidence Summit to review the knowledge and gaps on the utilization of financial incentives to enhance the quality and uptake of maternal healthcare. The goal was to provide donors and governments of the low- and middle-income countries with evidence informed recommendations on practice, policy, and strategies regarding the use of financial incentives, including vouchers, to enhance the demand and supply of maternal health services. The findings in this paper are intended to guide governments interested in maternal health voucher programmes with recommendations for sustainable implementation and impact. The Evidence Summit undertook a systematic review of five financing strategies. This paper presents the methods and findings for vouchers, building on a taxonomy to catalogue knowledge about voucher programme design and functionality. More than 120 characteristics under five major categories were identified: programme principles (objectives and financing); governance and management; benefits package and beneficiary targeting; providers (contracting and service pricing); and implementation arrangements (marketing, claims processing, and monitoring and evaluation). Among the 28 identified maternal health voucher programmes, common characteristics included: a stated objective to increase the use of services among the means-tested poor; contracted-out programme management; contracting either exclusively private facilities or a mix of public and private providers; prioritizing community-based distribution of vouchers; and tracking individual claims for performance purposes. Maternal voucher programmes differed on whether contracted providers were given training on clinical or administrative issues; whether some form of service verification was undertaken at facility or community level; and the relative size of programme management costs in the overall programme budget. Evidence suggests voucher programmes can serve populations with national-level impact. Reaching scale depends on whether the voucher programme can: (i) keep management costs low, (ii) induce a large demand-side response among the bottom two quintiles, and (iii) achieve a quality of care that translates a greater number of facility-based deliveries into a reduction in maternal morbidity and mortality

Internal quantum efficiencies of AlGaN quantum dots grown by molecular beam epitaxy and emitting in the UVA to UVC ranges

International audienceAlyGa1−yN quantum dots (QDs) have been grown by molecular beam epitaxy on AlxGa1−xN (0001) using a 2-dimensional–3-dimensional growth mode transition that leads to the formation of QDs. QDs have been grown for Al compositions y varying between 10% and 40%. The influence of the active region design [composition y, QD height, and bandgap difference (ΔEg) between the AlxGa1−xN cladding layer and the AlyGa1−yN QDs] is discussed based on microscopy, continuous wave photoluminescence (PL), and time-resolved PL (TRPL) mea- surements. In particular, increasing y leads to a shift of the QD emission toward shorter wavelengths, allowing covering a spectral range in the UV from 332 nm (UVA) to 276 nm (UVC) at room temperature (RT). The low-temperature (LT) internal quantum efficiency of the QD ensembles was estimated from TRPL experiments at 8 K and values between 11% and 66% were deduced. The highest internal quantum efficiency (IQE)-LT is found for the QDs with higher Al content y. Then, the PL spectrally integrated intensity ratios between RT and LT were measured to estimate the IQE of the samples at RT. The PL ratio is higher for larger ΔEg, for QDs with y of 0.1 or 0.2, and high PL intensity ratios up to 30% were also measured for QDs with larger y of 0.3 and 0.4. RT IQE values between 5% and 20% are deduced for AlyGa1−yN QDs emitting in the 276–308 nm range