Spike-timing-dependent plasticity: common themes and divergent vistas

Recent experimental observations of spike-timing-dependent synaptic plasticity (STDP) have revitalized the study of synaptic learning rules. The most surprising aspect of these experiments lies in the observation that synapses activated shortly after the occurrence of a postsynaptic spike are weakened. Thus, synaptic plasticity is sensitive to the temporal ordering of pre- and postsynaptic activation. This temporal asymmetry has been suggested to underlie a range of learning tasks. In the first part of this review we highlight some of the common themes from a range of findings in the framework of predictive coding. As an example of how this principle can be used in a learning task, we discuss a recent model of cortical map formation. In the second part of the review, we point out some of the differences in STDP models and their functional consequences. We discuss how differences in the weight-dependence, the time-constants and the non-linear properties of learning rules give rise to distinct computational functions. In light of these computational issues raised, we review current experimental findings and suggest further experiments to resolve some controversies.     

RNA and protein folding: common themes and variations

Visualizing the navigation of an ensemble of unfolded molecules through the bumpy energy landscape in search of the native state gives a pictorial view of biomolecular folding. This picture, when combined with concepts in polymer theory, provides a unified theory of RNA and protein folding. Just as for proteins, the major folding free energy barrier for RNA scales sublinearly with the number of nucleotides, which allows us to extract the elusive prefactor for RNA folding. Several folding scenarios can be anticipated by considering variations in the energy landscape that depend on sequence, native topology, and external conditions. RNA and protein folding mechanism can be described by the kinetic partitioning mechanism (KPM) according to which a fraction (Phi) of molecules reaches the native state directly, whereas the remaining fraction gets kinetically trapped in metastable conformations. For two-state folders Phi approximately 1. Molecular chaperones are recruited to assist protein folding whenever Phi is small. We show that the iterative annealing mechanism, introduced to describe chaperonin-mediated folding, can be generalized to understand protein-assisted RNA folding. The major differences between the folding of proteins and RNA arise in the early stages of folding. For RNA, folding can only begin after the polyelectrolyte problem is solved, whereas protein collapse requires burial of hydrophobic residues. Cross-fertilization of ideas between the two fields should lead to an understanding of how RNA and proteins solve their folding problems.     

Vertebrate floor-plate specification: variations on common themes

Situated at the ventral-most part of the vertebrate neural tube, the floor plate (FP) is an important signalling centre that controls the regional differentiation of neurons in the nervous system. It secretes guidance molecules that direct ventrally navigating axons crucial for the correct wiring of neuronal circuits. Although the function of the FP is well-conserved from fish to humans, discrepancies exists with respect to both the signalling system involved in FP induction, and the origin of the FP in various vertebrate species. Recent findings from the embryos of zebrafish, chicken and mouse provide insights that reconcile previous results and suggest common themes in vertebrate FP specification.     

Plant hormones and signaling: common themes and new developments

About 200 plant biologists convened in Keystone, Colorado, for the "Plant Hormones and Signaling" symposium, which was organized by Joanne Chory, Joe Ecker, and Mark Estelle. The meeting was run concurrently with the "Plant Innate Immunity" symposium organized by Jonathan Jones and Jane Glazebrook. In this report, we summarize the progress in plant hormones and signaling.     

Plagiarism and pathogenesis: common themes in actin remodeling.

The involvement of Nck in pedestal formation by EPEC highlights the similar strategies adopted by this bacterium and the Vaccinia virus to hijack the host cell's cytoskeleton.     

Protein translocation across membranes: common themes in divergent organisms

Specific signal sequences are required for the translocation of proteins into and across both the endoplasmic reticulum of eukaryotes and the plasma membrane of prokaryotes. The similar properties of these signals, together with their ability to function when transferred between systems, suggested that the mechanisms of translocation in the two cases may be fundamentally similar. Indeed, recent findings have revealed striking similarities between essential components of the prokaryotic and eukaryotic translocation systems, suggesting that both are derived from a common ancestor.     

The surprising proton channel: Novel insights into its structure and function

Commentary to: Tombola F, Ulbrich M, Isacoff I. The voltage-gated proton channel Hv1 has two pores, each controlled by one voltage sensor. Neuron 2008; 58:546-66.

Commentary to: Lee S-Y, Letts JA, MacKinnon R. Dimeric subunit stoichiometry of the human voltage-dependent proton channel Hv1. Proc Natl Acad Sci 2008; 105:7692-5.     

Novel proteases with unusual specificities

This review describes specific proteases that have been implicated in several interesting biological systems. Proteases have been selected for discussion in those instances where natural substrates appear to have been identified. The studies reviewed point to the critical role that proteases play in protein processing and degradation.     

Walking the walk: migration and other common themes in blood and vascular development

In this issue of Cell, a study by N. Cho and coworkers provides insight into the role of vascular endothelial growth factor (VEGF) signaling in Drosophila hematopoiesis. Their work suggests that an ancestral function of VEGF was to guide blood cell migration and highlights the conservation of at least one aspect of VEGF signaling during evolution.     

Novel functional assay for proteases and modulators

Proteases play a critical role in many cellular functions and have been an attractive therapeutic target due to their involvement in a number of disease processes. One prominent example is the secretases responsible for the generation of amyloid beta peptide, which is believed to be central for the development of Alzheimer's disease. It is therefore desirable to identify and characterize these proteases. We have developed a novel functional approach for identification of proteases and modulators by coupling the protease activity to caspase-mediated apoptosis. Here we show the proof of principle for this approach using beta-secretase as an example. We provide data showing that 1. A modified caspase-3 containing beta-secretase cleavage site induces apoptosis in 293T cells. 2. The modified caspase-3 induced apoptosis is correlated with the susceptibility of beta-secretase recognition sequence to beta-secretase. 3. In vivo beta-secretase competitors BACE2 and BACE2(D110A) prevent the modified caspase-3 induced cell death. Therefore, this approach can be a useful tool in studies of proteolytic cleavage provided only that the protease recognition sequence is known.     

Lysosomal cysteine proteases: structural features and their role in apoptosis

Among the variety of proteolytic enzymes enormous progress has been seen recently in our understanding of lysosomal cysteine proteases, also known as cysteine cathepsins. These enzymes play a crucial role in diverse biological processes in physiological and pathological states, including genetic diseases. In the present review, their properties and structural features that are important to an understanding of their biological function are presented. Special emphasis is given to the newly discovered role of lysosomal cathepsins in apoptotic pathways.     

Plant serine proteases: biochemical, physiological and molecular features.

In the latest two decades, the interest received by plant proteases has been on the rise. Serine proteases (EC 3.4.21)-in particular those from cucurbits, cereals and trees-share indeed a number of biochemical and physiological features, that may prove useful toward understanding of several mechanisms at the subcellular level. This critical review focuses on the characterization of most plant serine proteases, and comprehensively lists information produced by more and more sophisticated research tools that have led to the current state of the art in knowledge of these unique enzymes.     

Emerging common themes in regulation of PIKKs and PI3Ks

Phosphatidylinositol‐3 kinase‐related kinases (PIKKs) comprise a family of protein kinases that respond to various stresses, including DNA damage, blocks in DNA replication, availability of nutrients and errors in mRNA splicing. PIKKs are characterized by the presence of a conserved kinase domain (KD), whose activity is regulated by two C‐terminal regions, referred to as PIKK‐regulatory domain (PRD) and FRAP‐ATM‐TRRAP‐C‐terminal (FATC), respectively. Here, we review functional and structural data that implicate the PRD and FATC domains in regulation of PIKK activity, drawing parallels to phosphatidylinositol‐3 kinases (PI3K), lipid kinases that have sequence similarity to PIKKs. The PI3K C‐terminus, which we propose to be equivalent to the PRD and FATC domains of PIKKs, is in close proximity to the activation loop of the KD, suggesting that in PIKKs, the PRD and FATC domains may regulate kinase activity by targeting the activation loop.     

Individual and common inhibitors of coronavirus and picornavirus main proteases

Picornaviruses (PV) and coronaviruses (CoV) are positive-stranded RNA viruses which infect millions of people worldwide each year, resulting in a wide range of clinical outcomes. As reported in this study, using high throughput screening against ∼6800 small molecules, we have identified several novel inhibitors of SARS-CoV 3CL^pro with IC₅₀ of low μM. Interestingly, one of them equally inhibited both 3C^pro and 3CL^pro from PV and CoV, respectively. Using computer modeling, the structural features of these compounds as individual and common protease inhibitors were elucidated to enhance our knowledge for developing anti-viral agents against PV and CoV.     

Protein transport via amino-terminal targeting sequences: common themes in diverse systems (Review)

Many proteins that are synthesized in the cytoplasm of cells are ultimately found in non-cytoplasmic locations. The correct targeting and transport of proteins must occur across bacterial cell membranes, the endoplasmic reticulum membrane, and those of mitochondria and chloroplasts. One unifying feature among transported proteins in these systems is the requirement for an amino-terminal targeting signal. Although the primary sequence of targeting signals varies substantially, many patterns involving overall properties are shared. A recent surge in the identification of components of the transport apparatus from many different systems has revealed that these are also closely related. In this review we describe some of the key components of different transport systems and highlight these common features.     

Atomic structure and specificity of bacterial periplasmic receptors for active transport and chemotaxis: variation of common themes

Crystallographic structure refinement at very high resolutions of a dozen periplasmic receptors has revealed that, though they have different sizes (26 to 60kDa) and little sequence homology, they have high tertiary structure similarity. They consist of two distinct globular domains bisected by a cleft or groove wherein the ligand binds and is buried by a hinge-bending motion between the two domains. Structural analysis also reveals how hydrogen-bonding interactions can be tailored to a wide spectrum of specificity, ranging from the stringent specificity for phosphate and sulphate to the more loose specificity for peptides.     

Screening for modulators of cisplatin sensitivity: Unbiased screens reveal common themes

Cisplatin is a widely used chemotherapeutic agent to treat a variety of solid tumors. The cytotoxic mode of action of cisplatin is mediated by inducing conformational changes in DNA including intra- and inter-strand crosslink adducts. Recognition of these adducts results in the activation of the DNA damage response resulting in cell cycle arrest, repair, and potentially, apoptosis. Despite the clinical efficacy of cisplatin, many tumors are either intrinsically resistant or acquire resistance during treatment. The identification of cisplatin drug response modulators can help us understand these resistance mechanisms, provide biomarkers for treatment strategies, or provide drug targets for combination therapy. Here we discuss functional genetic screens, including one performed by us, set up to identify genes whose inhibition results in increased sensitivity to cisplatin. In summary, the validated genes identified in these screens mainly operate in DNA damage response including nucleotide excision repair, translesion synthesis, and homologous recombination.