Volume 2, Issue 5

Evolvability can be defined as the capacity of an individual to evolve and thus to capture adaptive mutations. Transposable elements (TE) are an important source of mutations in organisms. Their capacity to transpose within a genome, sometimes at a high rate, and their copy number regulation are environment-sensitive, as are the epigenetic pathways that mediate TE regulation in a genome. In this review we revisit the way we see evolvability with regard to transposable elements and epigenetics.

The fragile X family of genes encodes a small family of RNA binding proteins including FMRP, FXR1P and FXR2P that were identified in the 1990s. All three members are encoded by 17 exons and show alternative splicing at the 3′ ends of their respective transcripts. They share significant homology in the protein functional domains, including the Tudor domains, the nuclear localization sequence, a protein-protein interaction domain, the KH1 and KH2 domains and the nuclear export sequence. Fragile X family members are found throughout the animal kingdom, although all three members are not consistently present in species outside of mammals: only two family members are present in the avian species examined, Gallus gallus and Taeniopygia guttata, and in the frog Xenopus tropicalis . Although present in many tissues, the functions of the fragile X family members differ, which are particularly evident in knockout studies performed in animals. The fragile X family members play roles in normal neuronal function and in the case of FXR1, in muscle function.

Separation of metabolic pathways in organelles is critical for eukaryotic life. Accordingly, the number, morphology and function of organelles have to be maintained through processes linked with membrane remodeling events. Despite their acknowledged significance and intense study many questions remain about the molecular mechanisms by which organellar membranes proliferate. Here, using the example of peroxisome proliferation, we give an overview of how proteins elongate membranes. Subsequent membrane fission is achieved by dynamin-related proteins shared with mitochondria. We discuss basic criteria that membranes have to fulfill for these fission factors to complete the scission. Because peroxisome elongation is always associated with unequal distribution of matrix and membrane proteins, we propose peroxisomal division to be non-stochastic and asymmetric. We further show that these organelles need not be functional to carry on membrane elongation and present the most recent findings concerning members of the Pex11 protein family as membrane elongation factors. These factors, beside known proteins such as BAR-domain proteins, represent another family of proteins containing an amphipathic α-helix with membrane bending activity.

Members of the monoamine oxidase family of flavoproteins catalyze the oxidation of primary and secondary amines, polyamines, amino acids, and methylated lysine side chains in proteins. The enzymes have similar overall structures, with conserved flavin adenine dinucleotide (FAD)-binding domains and varied substrate-binding sites. Multiple mechanisms have been proposed for the catalytic reactions of these enzymes. The present review compares the structures of different members of the family and the various mechanistic proposals.

Disulfide bond formation in proteins is an effective tool of both structure stabilization and redox regulation. The prokaryotic periplasm and the endoplasmic reticulum of eukaryotes were long considered as the only compartments for enzyme mediated formation of stable disulfide bonds. Recently, the mitochondrial intermembrane space has emerged as the third protein-oxidizing compartment. The classic view on the mechanism of oxidative folding in the endoplasmic reticulum has also been reshaped by new observations. Moreover, besides the structure stabilizing function, reversible disulfide bridge formation in some proteins of the endoplasmic reticulum, seems to play a regulatory role. This review briefly summarizes the present knowledge of the redox systems supporting oxidative folding, emphasizing recent developments.

Originally, the finding of a particular distribution of cytidine-guanosine dinucleotides (CpGs) in genomic DNA was considered to be an interesting structural feature of eukaryotic genome organization. Despite a global depletion of CpGs, genes are frequently associated with CpG clusters called CpG islands (CGIs). CGIs are prevalently unmethylated but often found methylated in pathologic situations. On the other hand, CpGs outside of CGIs are generally methylated and are found mainly in the heterochromatic fraction of the genome. Hypomethylation of those CpGs is associated with genomic instability in malignancy. Additionally, CpG-rich and CpG-poor regions, as well as CpG-shores, are defined. Usually, the methylation status inversely correlates with gene expression. Methylation of CpGs, as well as demethylation and generation of hydroxmethyl-cytosines, is strictly regulated during development and differentiation. This review deals with the relevance of the organizational features of CpGs and their relation to each other.

Plants and bacteria respond to hyperosmotic stress by an increase in intracellular osmolality, adjusting their cell turgor to altered growth conditions. This can be achieved either by increased uptake or de novo synthesis of a variety of organic osmolytes (so-called ‘compatible solutes’), or by controlling fluxes of ions across cellular membranes. The relative contributions of each of these mechanisms have been debated in literature for many years and remain unresolved. This paper summarises all the arguments and reopens a discussion on the efficiency and strategies of osmotic adjustment in plants and bacteria. We show that the bulk of osmotic adjustment in both plants and bacteria is achieved by increased accumulation of inorganic osmolytes such as K + , Na + and Cl - . This is applicable to both halophyte and glycophyte species. At the same time, de novo synthesis of compatible solutes is an energetically expensive and slow option and can be used only for the fine adjustment of the cell osmotic potential. The most likely role the organic osmolytes play in osmotic adjustment is in osmoprotection of key membrane transport proteins and reactive oxygen species (ROS) scavenging. The specific mechanisms by which compatible solutes regulate activity of ion transporters remain elusive and require more thorough investigation. It is concluded that creating transgenic species with increased levels of organic osmolytes by itself is counterproductive due to high yield penalties; all these attempts should be complemented by a concurrent increase in the accumulation of inorganic ions directly used for osmotic adjustment.

There is increasing interest in the therapeutic targeting of proteases for the treatment of important diseases. Additionally new protein-based therapeutic strategies have the potential to widen the available treatments against these pathologies. In the last decade, accumulated evidence has confirmed that the family of proteases known as proprotein convertases (PCs) are potential targets for viral infections, osteoarthritis, cancer and cardiovascular disease, among others. Nevertheless, there are still many unanswered questions about the relevance of targeting PCs in a therapeutic context, especially regarding the anticipated secondary effects of treatment, considering the observed embryonic lethality of some PC knockout mice. In this review, the benefits of PCs as pharmacological targets will be discussed, with focus on concepts and strategies, as well as on the state of advancement of actual and future inhibitors.

Channeling of ions or substrates across membranes and enzymatic activity are two highly distinct biochemical concepts. They are usually studied by different research groups, which focus on either subject. Nature has provided a challenge for specialized scientists by fusing genes coding for a transmembrane channel domain with an enzyme domain. There are examples of fusion proteins consisting of an N-terminal ion channel or sensor and a C-terminal, cytosolic kinase domain (or other enzymes involved in signaling) of which either domain may influence the functionality of the other. The physiological role of such fusions may reside in coupling ion flux or membrane potential sensing to cellular responses or vice-versa. Other examples can be found in metabolism. We have identified and characterized an ar-senite-conducting aquaglyceroporin carrying a C-terminal ar-senate reductase domain. Here, a function in the detoxification of arsenic is obvious, with the enzyme domain generating the substrate for the channel domain, which immediately shuttles the toxic metabolite out of the cell. We see two advantages in this latter concept: lowering of the cellular toxicity due to rapid release of the substrate and energetic coupling of the reaction enthalpy to extrusion due to high local substrate gradients. In this overview, we summarize and discuss the current view on functional and physiological aspects of channel/enzyme fusion proteins.