Design principles of biochemical oscillators

Cellular rhythms are generated by complex interactions among genes, proteins and metabolites. They are used to control every aspect of cell physiology, from signalling, motility and development to growth, division and death. We consider specific examples of oscillatory processes and discuss four general requirements for biochemical oscillations: negative feedback, time delay, sufficient 'nonlinearity' of the reaction kinetics and proper balancing of the timescales of opposing chemical reactions. Positive feedback is one mechanism to delay the negative-feedback signal. Biological oscillators can be classified according to the topology of the positive- and negative-feedback loops in the underlying regulatory mechanism.     

A quantitative study of the division cycle of Caulobacter crescentus stalked cells

Progression of a cell through the division cycle is tightly controlled at different steps to ensure the integrity of genome replication and partitioning to daughter cells. From published experimental evidence, we propose a molecular mechanism for control of the cell division cycle in Caulobacter crescentus. The mechanism, which is based on the synthesis and degradation of three “master regulator” proteins (CtrA, GcrA, and DnaA), is converted into a quantitative model, in order to study the temporal dynamics of these and other cell cycle proteins. The model accounts for important details of the physiology, biochemistry, and genetics of cell cycle control in stalked C. crescentus cell. It reproduces protein time courses in wild-type cells, mimics correctly the phenotypes of many mutant strains, and predicts the phenotypes of currently uncharacterized mutants. Since many of the proteins involved in regulating the cell cycle of C. crescentus are conserved among many genera of α-proteobacteria, the proposed mechanism may be applicable to other species of importance in agriculture and medicine.     

Cu(II) organizes beta-2-microglobulin oligomers but is released upon amyloid formation

beta-2-Microglobulin (beta2m) is deposited as amyloid fibrils in the bones and joints of patients undergoing long-term dialysis treatment as a result of kidney failure. Previous work has shown that biologically relevant amounts of Cu(II) can cause beta2m to be converted to amyloid fibrils under physiological conditions in vitro. In this work, dynamic light scattering, mass spectrometry, and size-exclusion chromatography are used to characterize the role that Cu plays in the formation of oligomeric intermediates that precede fibril formation. Cu(II) is found to be necessary for the stability of the dimer and an initial form of the tetramer. The initially formed tetramer then undergoes a structural change to a state that no longer binds Cu(II) before progressing to a hexameric state. Based on these results, we propose that the lag phase associated with beta2m fibril formation is partially accounted for by the structural transition of the tetramer that results in Cu(II) loss. Consistent with this observation is the determination that the mature beta2m amyloid fibrils do not contain Cu. Thus, Cu(II) appears to play a catalytic role by enabling the organization of the necessary oligomeric intermediates that precede beta2m amyloid formation.     

The Effect of Habitat Fragmentation on Cyclic Population Dynamics: A Numerical Study

Through four spatially explicit models, we investigate how habitat fragmentation affects cyclic predator–prey population dynamics. We use a Partial Differential Equation (PDE) framework to describe the dispersal of predators and prey in a heterogeneous landscape made of high quality and low quality habitat patches, subject to increasing fragmentation through habitat separation and/or habitat loss. Our results show that habitat fragmentation decreases the amplitude of the predator–prey population cycles while average population density is not as strongly affected in general. Beyond these simple trends however, the four models show differing responses to fragmentation, indicating that when making predictions about population survival and persistence in the face of habitat fragmentation, the choice of model is important. Our results may inform conservation efforts in fragmented habitats for cyclic species such as the snowshoe hare and Canada lynx. Electronic Supplementary Material  The online version of this article () contains supplementary material, which is available to authorised users.     

Modelling the Canada lynx and snowshoe hare population cycle: the role of specialist predators

Mathematical models of the snowshoe hare (Lepus americanus) and Canada lynx (Lynx canadensis) population cycles in the boreal forest have largely focused on the interaction between a single specialist predator and its prey. Here, we consider the role that other hare predators play in shaping the cycles, using a predator–prey model for up to three separate specialist predators. We consider the Canada lynx, coyote (Canis latrans) and great horned owl (Bubo virginianus). Our model improves on past modelling efforts in two ways: (1) our model solutions more closely represent the boreal hare and predator cycles with respect to the cycle period, maximum and minimum hare densities and maximum and minimum predator densities for each predator, and (2) our model sheds light on the role each specialist plays in regulation of the hare cycle, in particular, the dynamics of the raptor appear to be crucial for characterising the low hare densities correctly.     

Distinct ligand specificity of the Tiam1 and Tiam2 PDZ domains

Guanine nucleotide exchange factor proteins of the Tiam family are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity. These proteins are modular and contain a variety of interaction domains, including a single post-synaptic density-95/discs large/zonula occludens-1 (PDZ) domain. Previous studies suggest that the specificities of the Tiam1 and Tiam2 PDZ domains are distinct. Here, we sought to conclusively define these specificities and determine their molecular origin. Using a combinatorial peptide library, we identified a consensus binding sequence for each PDZ domain. Analysis of these consensus sequences and binding assays with peptides derived from native proteins indicated that these two PDZ domains have overlapping but distinct specificities. We also identified residues in two regions (S(0) and S(-2) pockets) of the Tiam1 PDZ domain that are important determinants of ligand specificity. Site-directed mutagenesis of four nonconserved residues in these two regions along with peptide binding analyses confirmed that these residues are crucial for ligand affinity and specificity. Furthermore, double mutant cycle analysis of each region revealed energetic couplings that were dependent on the ligand being investigated. Remarkably, a Tiam1 PDZ domain quadruple mutant had the same specificity as the Tiam2 PDZ domain. Finally, analysis of Tiam family PDZ domain sequences indicated that the PDZ domains segregate into four distinct families based on the residues studied here. Collectively, our data suggest that Tiam family proteins have highly evolved PDZ domain-ligand interfaces with distinct specificities and that they have disparate PDZ domain-dependent biological functions.     

O-sulfonation of serine and threonine: mass spectrometric detection and characterization of a new posttranslational modification in diverse proteins throughout the eukaryotes

Protein sulfonation on serine and threonine residues is described for the first time. This post-translational modification is shown to occur in proteins isolated from organisms representing a broad span of eukaryote evolution, including the invertebrate mollusk Lymnaea stagnalis, the unicellular malaria parasite Plasmodium falciparum, and humans. Detection and structural characterization of this novel post-translational modification was carried out using liquid chromatography coupled to electrospray tandem mass spectrometry on proteins including a neuronal intermediate filament and a myosin light chain from the snail, a cathepsin-C-like enzyme from the parasite, and the cytoplasmic domain of the human orphan receptor tyrosine kinase Ror-2. These findings suggest that sulfonation of serine and threonine may be involved in multiple functions including protein assembly and signal transduction.