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The intracellular pathway that controls the cytoplasmic versus nuclear distribution of Gli transcriptional regulators in response to Hedgehog signaling remains poorly understood. Iguana appears to play a role in regulating this process independently of Hedgehog signaling.
The mitotic spindle assembly checkpoint arrests cells at metaphase by suppressing Cdc20, a protein required to trigger ubiquitination and consequent degradation of cyclin B. New evidence from Tang et al. appearing in the November 5th issue of Molecular Cell finds that one of the checkpoint proteins, Bub1, specifically phosphorylates Cdc20 to suppress APC/C activation.
Fatty acids have diverse roles in all cells. They are important as a source of energy, as structural components of cell membranes, as signalling molecules and as precursors for the synthesis of eicosanoids. Recent research has suggested that the organization of fatty acids into distinct cellular pools has a particularly important role in cells of the immune system and that forms of lipid trafficking exist, which are as yet poorly understood. This Review examines the nature and regulation of cellular lipid pools in the immune system, their delivery of fatty acids or fatty acid derivatives to specific locations and their potential role in health and disease.
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The HeadPiece (HP) domain, present in several F-actin-binding multi-domain proteins, features a well-conserved, solvent-exposed PXWK motif in its C-terminal subdomain. The latter is an autonomously folding subunit comprised of three alpha-helices organised around a hydrophobic core, with the sequence motif preceding the last helix. We report the contributions of each conserved residue in the PXWK motif to human villin HP function and structure, as well as the structural implications of the naturally occurring Pro to Ala mutation in dematin HP. NMR shift perturbation mapping reveals that substitution of each residue by Ala induces only minor, local perturbations in the full villin HP structure. CD spectroscopic thermal analysis, however, shows that the Pro and Trp residues in the PXWK motif afford stabilising interactions. This indicates that, in addition to the residues in the hydrophobic core, the Trp-Pro stacking within the motif contributes to HP stability. This is reinforced by our data on isolated C-terminal HP subdomains where the Pro is also essential for structure formation, since the villin, but not the dematin, C-terminal subdomain is structured. Proper folding can be induced in the dematin C-terminal subdomain by exchanging the Ala for Pro. Conversely, the reverse substitution in the villin C-terminal subdomain leads to loss of structure. Thus, we demonstrate a crucial role for this proline residue in structural stability and folding potential of HP (sub)domains consistent with Pro-Trp stacking as a more general determinant of protein stability.
Discovered in the 1970s, nuclear lamins control chromatin organization and are linked to many diseases. Zhang et al. now find that lamin A/C quantitatively constrains DNA replication initiation by limiting chromatin accessibility and sequestering proliferating cell nuclear antigen, extending lamin's long-known role in replication to the control of origin firing.
The genetic and histopathological backgrounds of adrenocortical tumorigenesis remain poorly characterized. In other tissues, there is conclusive evidence that hyperplasia and adenomas precede cancer. In the adrenal, there are few clinical cases of either hyperplasia or adenoma associated with later development of cancer, and there are few biological studies that attempt to characterize this process molecularly. Current research focuses on the early lesions of the adrenal cortex because of their possible molecular link with carcinogenesis, and evidence of their frequent association with atypical forms of Cushing's and Conn's syndromes, obesity, hypertension and/or diabetes. These studies indicate a model for oncogenesis that is the same as that in other tissues. The rarity of adrenal cancer compared to benign lesions could be a clue to unique features of adrenocortical cells. It might also highlight the function of genes that are associated with endocrine tumors in the context of which the concept of gene 'conductors' is introduced here.
A recent paper by Huber, Veinante and Stoop reports electrophysiological studies in slices of the amygdala in which the authors are able to demonstrate a cellular and spatial dissociation between the sites of action of oxytocin and vasopressin. These studies are important for determining how these brain peptides might gate autonomic responses to fear and other emotional stimuli.
Recently, rapid progress in our structural knowledge of K(+)-selective channels has started to provide a basis for comprehending the biophysical machinery underlying their electrophysiological properties. These studies have begun to reveal how a diverse array of distinct, cytoplasmically positioned domains affect the activity of associated channels. Some of these establish functional diversity by selectively mediating channel assembly. More importantly, these cytoplasmic domains couple intracellular signals to the gating of their associated pore. New structural insights are providing a clearer understanding of the fundamental molecular mechanisms of these K(+) channels that, in turn, partly underlie complex neurological phenomena.
Two of the physiologically important processes that take place in biological membranes are the partitioning of water-soluble proteins into the membrane and the sequestering of specific transmembrane proteins into membrane microdomains or 'rafts'. Although these two processes often involve different classes of protein, recent biophysical studies indicate that they both strongly depend on the structural and elastic properties of the membrane bilayer. That is, both the partitioning of peptides into membranes and the distribution of transmembrane peptides in the plane of the membrane are modulated by physical properties of the lipid bilayer that are controlled by cholesterol content and the composition of the phospholipid hydrocarbon chain.
Lipopolysaccharide (LPS) from the outer cell wall of Gram-negative bacteria is a potent stimulator of the mammalian innate immune system. The Toll-like receptor 4 (TLR4) pathway triggers the inflammatory responses induced by LPS in a process that requires the interaction of LPS-bound myeloid differentiation-2 (MD-2) with TLR4. Here we propose two possible mechanisms for LPS recognition and signalling that take into account both the structural information available for TLR4 and MD-2, and the determinants of endotoxicity, namely, the acylation and phosphorylation patterns of LPS. In our first model, LPS induces the association of two TLR4-MD-2 heterodimers by binding to two different molecules of MD-2 through the acyl chains of lipid A. In our second model, the binding of LPS to a single TLR4-MD-2 complex facilitates the recruitment of a second TLR4-MD-2 heterodimer. These models contrast with the activation of Drosophila Toll, where the receptor is crosslinked by a dimeric protein ligand.
Ca2+ channels in the plasma membrane of T cells vitally influence Ca2+-dependent signals that lead ultimately to cytokine secretion, cellular proliferation and apoptosis. Conventional models depict the Ca2+ inrush across the T-cell membrane following T-cell receptor engagement as being due to Ca2+-release-activated Ca2+ (CRAC) channels. A poorly understood mechanism detects the lowered Ca2+ concentrations within intracellular stores that open CRAC channels. Mammalian homologs of the Drosophila transient receptor potential Ca2+ channels possibly help to gate the store-operated, Ca2+-borne CRAC current. In this article, we review evidence of a supplementary involvement of other Ca2+ channels, the opening of which does not necessarily reflect intracellular Ca2+-store depletion. We highlight a role for variants of L-type voltage-dependent Ca2+ channels in increasing intracellular Ca2+ concentrations during activation. For more-accurate modeling of lymphocyte activation and possible pharmacological interventions, future research should aim to identify physiologically relevant situations in which such channels help to shape the Ca2+ signal.
Centrins are members of a highly conserved subgroup of the EF-hand superfamily of Ca(2+)-binding proteins commonly associated with centrosome-related structures. In the retina, centrins are also prominent components of the photoreceptor cell ciliary apparatus. Centrin isoforms are differentially localized at the basal body and in the lumen of the connecting cilium. All molecular exchanges between the inner and outer segments occur through this narrow connecting cilium. Ca(2+)-activated centrin isoforms bind to the visual heterotrimeric G-protein transducin via an interaction with the betagamma-subunit. Ca(2+)-dependent assemblies of centrin/G-protein complexes may regulate the transducin movement through the connecting cilium. Formation of this complex represents a novel mechanism in regulation of translocation of signaling proteins in sensory cells, as well as a potential link between molecular trafficking and signal transduction in general.
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OBJECTIVES: To review 12 patients with a clinicopathogenic diagnosis of xanthogranulomatous pyelonephritis (XGP) and to determine if a computed tomography (CT) scan is the imaging procedure of choice for diagnosis. METHODS: A retrospective review, over the last 12 years, of patients with XGP at our institution. RESULTS: Nine of 10 patients (90%) who were evaluated by CT scan had the correct diagnosis made prior to nephrectomy. The most common presenting symptoms and signs were flank pain (64%), leukocytosis (73%), and anemia (82%). Seventy-five percent of the patients had a ureteropelvic junction stone or a staghorn stone in the affected kidney at the time of clinical presentation. Proteus was the most common organism cultured. CONCLUSIONS: After reviewing the clinical features of these 12 patients, we recommended CT scan to evaluate the patient in whom clinical suspicion of XGP is entertained. CT has proven to be the most accurate imaging study to evaluate this disease.
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