Interaction of Serum- and Glucocorticoid Regulated Kinase 1 (SGK1) with the WW-Domains of Nedd4-2 Is Required for Epithelial Sodium Channel Regulation

The epithelial sodium channel (ENaC) is an integral component of the pathway for Na(+) absorption in epithelial cells. The ubiquitin ligases Nedd4 and Nedd4-2 bind to ENaC and decrease its activity. Conversely, Serum- and Glucocorticoid regulated Kinase-1 (SGK1), a downstream mediator of aldosterone, increases ENaC activity. This effect is at least partly mediated by direct interaction between SGK and Nedd4-2. SGK binds both Nedd4 and Nedd4-2, but it is only able to phosphorylate Nedd4-2. Phosphorylation of Nedd4-2 reduces its ability to bind to ENaC, due to the interaction of phosphorylated Nedd4-2 with 14-3-3 proteins, and hence increases ENaC activity. WW-domains in Nedd4-like proteins bind PY-motifs (PPXY) present in ENaC subunits, and SGK also has a PY-motif.Here we show that single or tandem WW-domains of Nedd4 and Nedd4-2 mediate binding to SGK and that different WW-domains of Nedd4 and Nedd4-2 are involved. Our data also show that WW-domains 2 and 3 of Nedd4-2 mediate the interaction with SGK in a cooperative manner, that activated SGK has increased affinity for the WW-domains of Nedd4-2 in vitro, and a greater stimulatory effect on ENaC Na(+) transport compared to wildtype SGK. Further, SGK lacking a PY motif failed to stimulate ENaC activity in the presence of Nedd4-2.Binding of Nedd4-2 WW-domains to SGK is necessary for SGK-induced ENaC activity

Alkenylphosphonates: unexpected products from reactions of methyl 2-[(diethoxyphosphoryl)methyl]benzoate under Horner–Wadsworth–Emmons conditions

International audienc

Purification and characterisation of a novel cysteine conjugate β-lyase from the tapeworm <i>Moniezia expansa</i>

The paper presents the first report of the purification of an invertebrate cysteine conjugate ?-lyase (CCBL). CCBL activity was shown to predominate within the cytosolic fraction of tissue from the tapeworm Moniezia expansa. The monomeric cytosolic enzyme was isolated with a Mr of 72 kDa and co-purified with transaminase activity towards l-aspartate. The substrate profile for M. expansa CCBL is different from that of mammalian CCBLs. Exploiting the differences in mammalian and parasite substrate profiles will facilitate the development of helminth targeted conjugates which will not be activated by host (mammalian) CCBLsPeer reviewe

The relationship between non-elite sporting activity and calcaneal bone density in adolescents and young adults: a narrative systematic review

Introduction: osteoporotic fractures represent a major public health burden. The risk of fragility fractures in late adulthood is strongly impacted by peak bone mass acquisition by the third decade. Weight-bearing sporting activity may be beneficial to peak bone mass accrual, but previous studies have focused on elite sporting activity and have used dual energy X-ray absorptiometry as a measure of bone density. The authors performed a narrative systematic review of individual sports (performed non-competitively or at local level) and calcaneal quantitative ultrasound (cQUS) bone measures in young people.Methods: multiple databases were systematically searched up until the 31st of March 2019. The authors included studies of participants' mean age (11–35 years), reporting any level of recreational sporting activity and cQUS measures as well as excluding elite/professional sporting physical activity. Studies (title and abstract) were screened independently by two reviewers, and a third reviewer resolved any discrepancies. STROBE guidelines were used to check the reporting of observational studies. The Newcastle–Ottawa Scale was used to assess the risk of bias of the studies included in the review. The systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO).Results: a search yielded 29,512 articles that considered relationships between bone density assessed by any technique and sporting activity. Duplicate and out of scope abstracts were removed. This left 424 papers that were screened by two reviewers; of these, six met the inclusion criteria, including assessment by cQUS. The authors identified papers where sports were considered, included soccer (football), swimming, cycling, gymnastics, dancing, badminton, basketball, fencing, wrestling, and judokas. Although study heterogeneity prohibited meta-analysis, all six included studies reported significant benefits of weight-bearing non-elite sports on cQUS outcomes.Conclusion: our study found beneficial effects of non-elite sports participation on cQUS in adolescence and young adulthood, although further work is now indicated