The structure of Tap42/alpha4 reveals a tetratricopeptide repeat-like fold and provides insights into PP2A regulation

Physiological functions of protein phosphatase 2A (PP2A) are determined via the association of its catalytic subunit (PP2Ac) with diverse regulatory subunits. The predominant form of PP2Ac assembles into a heterotrimer comprising the scaffolding PR65/A subunit together with a variable regulatory B subunit. A distinct population of PP2Ac associates with the Tap42/alpha4 subunit, an interaction mutually exclusive with that of PR65/A. Tap42/alpha4 is also an interacting subunit of the PP2Ac-related phosphatases, PP4 and PP6. Tap42/alpha4, an essential protein in yeast and suppressor of apoptosis in mammals, contributes to critical cellular functions including the Tor signaling pathway. Here, we describe the crystal structure of the PP2Ac-interaction domain of Saccharomyces cerevisiae Tap42. The structure reveals an all alpha-helical protein with striking similarity to 14-3-3 and tetratricopeptide repeat (TPR) proteins. Mutational analyses of structurally conserved regions of Tap42/alpha4 identified a positively charged region critical for its interactions with PP2Ac. We propose a scaffolding function for Tap42/alpha4 whereby the interaction of PP2Ac at its N-terminus promotes the dephosphorylation of substrates recruited to the C-terminal region of the molecule.     

Spanish late Pliocene and early Pleistocene hominid, palaeolithic and faunal finds from Orce (Granada) and Cueva Victoria (Murcia)

In SE Spain, recent excavations in the Orce basin and at Cueva Victoria indicate presence of both hominids and hominid activity from the Plio-Pleistocene boundary and early Lower Pleistocene.     

Unwrapping Neurotrophic Cytokines and Histone Modification

The conventional view that neuroinflammatory lesions contain strictly pro- and anti-inflammatory cytokines is being challenged. Some proinflammatory products e.g. TNF-α are crucial intermediates in axon regeneration, oligodendroglial renewal and remyelination. A more functional system of nomenclature classifies cytokines by their neuro ‘protective’ or ‘suppressive’ properties. Beyond the balance of these ‘environmental’ or ‘extrinsic’ signals, specific ‘intrinsic’ determinants of cytokine signalling appear to influence the outcome of axoglial regeneration. In this commentary, we examine the potential importance of cytokine-induced histone modification on oligodendrocyte differentiation. Neuroinflammation mediates the release of astrocytic leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which potentiates oligodendrocyte differentiation and myelin production. Meanwhile, histone deacetylation strongly suppresses important inhibitors of oligodendrocyte differentiation. Given that LIF and EPO induce histone deacetylases in other systems, future studies should examine whether this mechanism significantly influences the outcome of cytokine-induced remyelination, and whether epigenetic drug targets could potentiate the effects of exogenous cytokine therapy.     

Energy and water flux during terrestrial estivation and overland movement in a freshwater turtle

The doubly labeled water (DLW) method for studying energy and water balance in field-active animals is not feasible for freshwater animals during aquatic activities, but several species of nominally aquatic reptiles leave wetlands for several critical and extended behaviors, where they face challenges to their energy and water balance. Using DLW, we studied energy and water relations during terrestrial estivation and movements in the eastern long-necked turtle (Chelodina longicollis), a species that inhabits temporary wetlands in southeastern Australia. Water efflux rates of 14.3-19.3 mL (kg d)(-1 ) during estivation were nearly offset by influx, indicating that turtles did not maintain water balance while terrestrial, though dehydration was slow. Estivation energy expenditure declined over time to 20.0-24.6 kJ (kg d)(-1) but did not indicate substantial physiological specializations. Energy reserves are predicted to limit survival in estivation to an estimated 49-261 d (depending on body fat), which is in close agreement with observed bouts of natural estivation in this population. The energy cost and water flux rates associated with overland movement behavior ranged from 46 to 99 kJ (kg d)(-1 ) and from 21.6 to 40.6 mL (kg d)(-1), respectively, for turtles moving 23-34 m d(-1). When a wetland dries, a turtle that forgoes movement to other wetlands can save sufficient energy to fuel up to 134 d in estivation. The increasing time in estivation with travel distance gained in this energy "trade-off" fits our previous observations that more turtles estivate when longer distances must be traveled to the nearest permanent lake, whereas emigration is nearly universal when only short distances must be traversed. The DLW method shows promise for addressing questions regarding the behavioral ecology and physiology of freshwater turtles in terrestrial situations, though validation studies are needed.     

When BAD is good for beta cells

BAD, a proapoptotic member of the Bcl-2 family of proteins, is regulated by phosphorylation. A recent study (Danial et al., 2008) suggests a phosphorylation-state-dependent bifunctional role of BAD in the regulation of glucose-stimulated insulin secretion and beta cell mass.