Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action.

Immunophilin is the collective name given to the cyclophilin and FK506-binding protein (FKBP) families. As the name suggests, these include the major binding proteins of certain immunosuppressive drugs: cyclophilins for the cyclic peptide cyclosporin A and FKBPs for the macrolactones FK506 and rapamycin. Both families, although dissimilar in sequence, possess peptidyl-prolyl <i>cis-trans</i> isomerase activity in vitro and can play roles in protein folding and transport, RNA splicing and the regulation of multiprotein complexes in cells. In addition to enzymic activity, many immunophilins act as molecular chaperones. This property may be conferred by the isomerase domain and/or by additional domains. Recent years have seen a great increase in the number of known immunophilin genes in parasitic protozoa and helminths and in many cases their products have been characterized biochemically and their temporal and spatial expression patterns have been examined. Some of these genes represent novel types: one example is a <i>Toxoplasma gondii</i> gene encoding a protein with both cyclophilin and FKBP domains. Likely roles in protein folding and oligomerisation, RNA splicing and sexual differentiation have been suggested for parasite immunophilins. In addition, unexpected roles in parasite virulence (Mip FKBP of <i>Trypanosoma cruzi</i>) and host immuno-modulation (e.g. 18-kDa cyclophilin of <i>Toxoplasma gondii</i>) have been established. Furthermore, in view of the potent antiparasitic activities of cyclosporins, macrolactones and nonimmunosuppressive derivatives of these compounds, immunophilins may mediate drug action and/or may themselves represent potential drug targets. Investigation of the mechanisms of action of these agents may lead to the design of potent and selective antimalarial and other antiparasitic drugs. This review discusses the properties of immunophilins in parasites and the 'animal model' <i>Caenorhabditis elegans</i> and relates these to our understanding of the roles of these proteins in cellular biochemistry, host-parasite interaction and the antiparasitic mechanisms of the drugs that bind to them

TWISTED DWARF1 mediates the action of auxin transport inhibitors on actin cytoskeleton dynamics

Plant growth and architecture is regulated by the polar distribution of the hormone auxin. Polarity and flexibility of this process is provided by constant cycling of auxin transporter vesicles along actin filaments, coordinated by a positive auxin-actin feedback loop. Both polar auxin transport and vesicle cycling are inhibited by synthetic auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA), counteracting the effect of auxin; however, underlying targets and mechanisms are unclear. Using NMR, we map the NPA binding surface on the Arabidopsis thaliana ABCB chaperone TWISTED DWARF1 (TWD1). We identify ACTIN7 as a relevant, although likely indirect, TWD1 interactor, and show TWD1-dependent regulation of actin filament organization and dynamics and that TWD1 is required for NPA-mediated actin cytoskeleton remodeling. The TWD1-ACTIN7 axis controls plasma membrane presence of efflux transporters, and as a consequence act7 and twd1 share developmental and physiological phenotypes indicative of defects in auxin transport. These can be phenocopied by NPA treatment or by chemical actin (de)stabilization. We provide evidence that TWD1 determines downstream locations of auxin efflux transporters by adjusting actin filament debundling and dynamizing processes and mediating NPA action on the latter. This function appears to be evolutionary conserved since TWD1 expression in budding yeast alters actin polarization and cell polarity and provides NPA sensitivity

Breast density measurements with ultrasound tomography: A comparison with film and digital mammography

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134902/1/mp2057.pd

Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses

Gephyrin is a multifunctional scaffold protein essential for accumulation of inhibitory glycine and GABAA receptors at post-synaptic sites. The molecular events involved in gephyrin-dependent GABAA receptor clustering are still unclear. Evidence has been recently provided that gephyrin phosphorylation plays a key role in these processes. Gephyrin post-translational modifications have been shown to influence the structural remodeling of GABAergic synapses and synaptic plasticity by acting on post-synaptic scaffolding properties as well as stability. In addition, gephyrin phosphorylation and the subsequent phosphorylation-dependent recruitment of the chaperone molecule Pin1 provide a mechanism for the regulation of GABAergic signaling. Extensively characterized as pivotal enzyme controlling cell proliferation and differentiation, the prolyl-isomerase activity of Pin1 has been shown to regulate protein synthesis necessary to sustain the late phase of long-term potentiation at excitatory synapses, which suggests its involvement at synaptic sites. In this review we summarize the current state of knowledge of the signaling pathways responsible for gephyrin post-translational modifications. We will also outline future lines of research that might contribute to a better understanding of molecular mechanisms by which gephyrin regulates synaptic plasticity at GABAergic synapses. \ua9 2014 Zacchi, Antonelli and Cherubini

NMR assignments of the FKBP-type PPIase domain of FKBP42 from Arabidopsis thaliana

The Atfkbp42 gene is associated with reduced and disoriented growth of Arabidopsis thaliana. Resonance assignments are reported for the FKBP-type PPIase domain of AtFKBP42. Signal intensities reveal an additional structure element that is atypical for such FKBP domains