Evolution of protein families: is it possible to distinguish between domains of life?

Understanding evolutionary relationships between species can shed new light into the rooting of the tree of life and the origin of eukaryotes, thus, resulting in a long standing interest in accurately assessing evolutionary parameters at time scales on the order of a billion of years. Prior work suggests large variability in molecular substitution rates, however, we still do not know whether such variability is due to species-specific trends at a genomic scale, or whether it can be attributed to the fluctuations inherent in any stochastic process. Here, we study the statistical properties of gene and protein-family sizes in order to quantify the long time scale evolutionary differences and similarities across species. We first determine the protein families of 209 species of bacteria and 20 species of archaea. We find that we are unable to reject the null hypothesis that the protein-family sizes of these species are drawn from the same distribution. In addition, we find that for species classified in the same phylogenetic branch or in the same lifestyle group, family size distributions are not significantly more similar than for species in different branches. These two findings can be accounted for in terms of a dynamical birth, death, and innovation model that assumes identical protein-family evolutionary rates for all species. Our theoretical and empirical results thus strongly suggest that the variability empirically observed in protein-family size distributions is compatible with the expected stochastic fluctuations for an evolutionary process with identical genomic evolutionary rates. Our findings hold special importance for the plausibility of some theories of the origin of eukaryotes which require drastic changes in evolutionary rates for some period during the last 2 billion years.     

Interactions between prion protein isoforms: the kiss of death?

Direct interactions between the normal and aberrant forms of prion protein appear to be crucial in the transmission and pathogenesis of transmissible spongiform encephalopathies (TSEs) or prion diseases. Recent studies of such interactions in vitro have provided mechanistic insight into how TSE-associated prion protein might promote its own propagation in a manner that is specific enough to account, at least in part, for TSE strains and species barriers.     

Autophagy: dual roles in life and death?

Autophagy is an evolutionarily conserved mechanism for the degradation of cellular components in the cytoplasm, and serves as a cell survival mechanism in starving cells. Recent studies indicate that autophagy also functions in cell death, but the precise role of this catabolic process in dying cells is not clear. Here I discuss the possible roles for autophagy in dying cells and how understanding the relationship between autophagy, cell survival and cell death is important for health and development.     

Daxx: death or survival protein?

The death domain-associated protein (Daxx) was originally cloned as a CD95 (FAS)-interacting protein and modulator of FAS-induced cell death. Daxx accumulates in both the nucleus and the cytoplasm; in the nucleus, Daxx is found associated with the promyelocytic leukaemia (PML) nuclear body and with alpha-thalassemia/mental retardation syndrome protein (ATRX)-positive heterochromatic regions. In the cytoplasm, Daxx has been reported to interact with various proteins involved in cell death regulation. Despite a significant number of studies attempting to determine Daxx function in apoptotic and non-apoptotic cell death, its precise role in this process is only partially understood. Here, we critically review the current understanding of Daxx function and shed new light on this interesting field.     

Autism and X-linked hypophosphatemia: A possible association?

We herein report the joint occurrence of an autistic disorder (AD) and X-linked hypophosphatemia. X-linked hypophosphatemia (XLH), an X-linked dominant disorder, is the most common of the inherited renal phosphate wasting disorders. Autism is a pervasive developmental disorder that occurs mainly due to genetic causes. In approximately 6-15% of cases, the autistic phenotype is a part of a broader genetic condition called syndromic autism.Therefore, reports of cases with the joint occurrence of a known genetic syndrome and a diagnosis of ASD by a child psychiatrist are relevant. A joint occurrence does not, however, mean that there is always a causal link between the genetic syndrome and the autistic behavioural phenotype. In this case, there are a number of arguments countering a causal link.     

The binary switch that controls the life and death decisions of ER stressed β cells

Diabetes mellitus is a group of common metabolic disorders defined by hyperglycemia. One of the most important factors contributing to hyperglycemia is dysfunction and death of β cells. Increasing experimental, clinical, and genetic evidence indicates that endoplasmic reticulum (ER) stress plays an important role in β cell dysfunction and death during the progression of type 1 and type 2 diabetes as well as genetic forms of diabetes such as Wolfram syndrome. The mechanisms of ER stress-mediated β cell dysfunction and death are complex and not homogenous. Here we review the recent key findings on the role of ER stress and the unfolded protein response (UPR) in β cells and the mechanisms of ER stress-mediated β cell dysfunction and death. Complete understanding of these mechanisms will lead to novel therapeutic modalities for diabetes.     

Interactions between misfolded protein oligomers and membranes: A central topic in neurodegenerative diseases?

The deposition of amyloid material has been associated with many different diseases. Although these diseases are very diverse the amyloid material share many common features such as cross-β-sheet structure of the backbone of the proteins deposited. Another common feature of the aggregation process for a wide variety of proteins is the presence of prefibrillar oligomers. These oligomers are linked to the cytotoxicity occurring during the aggregation of proteins. These prefibrillar oligomers interact extensively with lipid membranes and in some cases leads to destabilization of lipid membranes. This interaction is however highly dependent on the nature of both the oligomer and the lipids. Anionic lipids are often required for interaction with the lipid membrane while increased exposure of hydrophobic patches from highly dynamic protein oligomers are structural determinants of cytotoxicity of the oligomers. To explore the oligomer lipid interaction in detail the interaction between oligomers of α-synuclein and the 4th fasciclin-1 domain of TGFBIp with lipid membranes will be examined here. For both proteins the dynamic species are the ones causing membrane destabilization and the membrane interaction is primarily seen when the lipid membranes contain anionic lipids. Hence the dynamic nature of oligomers with exposed hydrophobic patches alongside the presence of anionic lipids could be essential for the cytotoxicity observed for prefibrillar oligomers in general. This article is part of a Special Issue entitled: Lipid–protein interactions.     

Force spectroscopy studies on protein–ligand interactions: A single protein mechanics perspective

Protein–ligand interactions are ubiquitous and play important roles in almost every biological process. The direct elucidation of the thermodynamic, structural and functional consequences of protein–ligand interactions is thus of critical importance to decipher the mechanism underlying these biological processes. A toolbox containing a variety of powerful techniques has been developed to quantitatively study protein–ligand interactions in vitro as well as in living systems. The development of atomic force microscopy-based single molecule force spectroscopy techniques has expanded this toolbox and made it possible to directly probe the mechanical consequence of ligand binding on proteins. Many recent experiments have revealed how ligand binding affects the mechanical stability and mechanical unfolding dynamics of proteins, and provided mechanistic understanding on these effects. The enhancement effect of mechanical stability by ligand binding has been used to help tune the mechanical stability of proteins in a rational manner and develop novel functional binding assays for protein–ligand interactions. Single molecule force spectroscopy studies have started to shed new lights on the structural and functional consequence of ligand binding on proteins that bear force under their biological settings.     

The RAD6 gene of yeast: A link between DNA repair,chromosome structure and protein degradation?

Summary Among the DNA repair mutants of the yeastSaccharomyces cerevisiae, the rad6 mutants are characterized by a highly pleiotropic phenotype. Most remarkably, these mutants are sensitive towards a variety of DNA-damaging agents and deficient in mutation induction. The RAD6 gene has been cloned and most recently, ubiquitin-conjugating activity of the Rad6 protein has been demonstrated. In this brief review, the properties of rad6 mutants are discussed in the light of these new findings. The available data hint at a connection between DNA repair, mutagenesis, chromosome structure and protein degradation.     

Mouse models to study polycystic ovary syndrome: A possible link between metabolism and ovarian function?

Polycystic ovary syndrome (PCOS) is the most common cause of female infertility affecting 6–8% of women worldwide. PCOS is characterized by two of the following three criteria: clinical or biochemical hyperandrogenism, oligo- or amenorrhea, and polycystic ovaries (PCO). In addition, women with PCOS are often obese and insulin resistant, and are at risk for type 2 diabetes and cardiovascular disease. The etiology of PCOS remains unknown. Therefore, several animal models for PCOS have been generated to gain insight into the etiology and development of the PCOS-associated phenotypes. Androgens are considered the main culprit of PCOS, and therefore, androgenization of animals is the most frequently used approach to induce symptoms that resemble PCOS. Prenatal or prepubertal androgen treatment results in many characteristics of human PCOS, including anovulation, cyst-like follicles, elevated luteinizing hormone (LH) levels, increased adiposity, and insulin insensitivity. However, PCOS has a heterogeneous presentation, and therefore it is difficult to generate a model that exactly reproduces the reproductive and metabolic phenotypes observed in women with PCOS. In this review, we discuss several mouse models for PCOS, and compare the reproductive and/or metabolic phenotypes observed in several androgen-induced models as well as in several genetic models.     

Integrin clipping: A novel adhesion switch?

During human prostate cancer progression, the majority of normally expressed integrins are suppressed with the exception of the alpha6, alpha3, and beta1 integrins. We have shown that in prostate cancer, the alpha6 integrin is found paired with the beta1 integrin and that a novel form of the alpha6 integrin that lacks a large portion of the extracellular domain (alpha6p) exists. The alpha6pbeta1 integrin is found in human prostate cancer tissue specimens as well as tissue culture cell lines and is formed on the cell surface. This review discusses the mechanism of alpha6pbeta1 production and the potential functions of this integrin variant. Our current working model predicts that the alpha6pbeta1 integrin maintains the intracellular cytoskeletal connections associated with the heterodimer while allowing for an alteration in cell adhesion. The mechanism provides a selective advantage for cancer cell metastasis.     

Cell size: a matter of life or death?

Proper growth and development of multicellular organisms require the tight regulation of cell growth, cell division and cell death. A recent study has identified a novel regulatory link between two of these processes: cell growth and cell death.     

What are the relations between mechanics, gait parameters, and energetics in terrestrial locomotion?

Are the different energy-conserving mechanics (i.e., pendulum and spring) used in different gaits reflected in differences in energetics and/or stride parameters? The analysis included published data from several species and new data from horses. When changing from pendulum to spring mechanics, there is a change in the slope of metabolic rate (MR) vs. speed in all species, in birds and quadrupeds there is no step increase, and in humans there are conflicting reports. At the trot-gallop transition, where quadrupeds are hypothesized to change from spring mechanics to some combination of spring and pendulum mechanics, there is a change in slope of MR vs. speed in horses but not in other species. Stride frequency (SF) is a logarithmic function of walking speed in all species, a linear function of trotting/running speed, and nearly independent of speed in galloping. In humans and horses there is a discontinuity in SF at the walk-trot (run) transition but not in birds. The slope of time of contact vs. speed does not change with mechanics in most species, but it does in humans. In horses and humans, there is a discontinuity at the walk-trot (run) transition and data for other species do not permit generalization. Duty factor (DF) in humans is greater than 0.5 in walking (pendulum mechanics) and less than 0.5 when running (spring mechanics). However, this is not true in many species that have DF>0.5 at the lowest speeds where they use spring mechanics. When trotting at low speeds, horses use forelimb DF>0.5 and hind limb DF<0.5. Thus, it is confusing to distinguish between walking and running by DF.     

Autophagy in Apicomplexa: a life sustaining death mechanism?

Programmed cell death (PCD) pathways remain understudied in parasitic protozoa in spite of the fact that they provide potential targets for the development of new therapy. The best understood PCD pathway in higher eukaryotes is apoptosis although emerging evidence also points to autophagy as a mediator of death in certain physiological contexts. Bioinformatic analyses coupled with biochemical and cell biological studies suggest that parasitic protozoa possess the capacity for PCD including a primordial form of apoptosis. Recent work in Toxoplasma and emerging data from Plasmodium suggest that autophagy-related processes may serve as an additional death promoting pathway in Apicomplexa. Detailed mechanistic studies into the molecular basis for PCD in parasitic protozoa represent a fertile area for investigation and drug development.     

Motor neuron diseases and neurotoxic substances: A possible link?

The motor neuron diseases (MNDs) are a group of related neurodegenerative diseases that cause the relative selective progressive death of motor neurons. Exploring the molecular mechanisms underlying MND phenotypes has been hampered by their multifactorial nature and high incidence of sporadic cases, although genetic factors are considered to play a considerable role at present. However, environmental factors, especial exposure to neurotoxic substances, could induce neurotoxicity with the same phenotypes of specific MNDs. Organophosphate-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterized by ataxia and progression to paralysis, with a concomitant distal axonal degeneration and secondary demyelination of central and peripheral axons. The inhibition and subsequent aging of neuropathy target esterase (NTE) by organophosphate has been proposed to be the initiating event in OPIDN. NTE is characterized to be a lysophospholipase/phospholipase B mostly in the nervous system to regulate phospholipid homeostasis. Brain-specific deletion of mouse NTE contributes to the behavioral defects characterized by neuronal loss. Recently, mutations in human NTE have also been shown to cause a hereditary spastic paraplegia called NTE-related motor neuron disorder with the same characteristics of OPIDN, which supported the role of NTE abnormalities in OPIDN, and raised the possibility that NTE pathway disturbances contribute to other MNDs. Together with the identified association of paraoxonase polymorphisms with amyotrophic lateral sclerosis, there is a possibility that neurotoxic substances contribute to MND in genetically vulnerable people by gene-environment interactions.