Gender as a historical kind: a tale of two genders?

Is there anything that members of each binary category of gender have in common? Even many non-essentialists find the lack of unity within a gender worrying as it undermines the basis for a common political agenda for women. One promising proposal for achieving unity is by means of a shared historical lineage of cultural reproduction with past binary models of gender (e.g. Bach in Ethics 122:231–272, 2012). I demonstrate how such an account is likely to take on board different binary and also non-binary systems of gender. This implies that all individuals construed as members of the category, “women” are in fact not members of the same historical kind after all! I then consider different possible means of modifying the account but conclude negatively: the problem runs deeper than has been appreciated thus far.     

The PASTA domain: a β-lactam-binding domain

The PASTA domain (for penicillin-binding protein and serine/threonine kinase associated domain) is found in the high molecular weight penicillin-binding proteins and eukaryotic-like serine/threonine kinases of a range of pathogens. We describe this previously uncharacterized domain and infer that it binds β-lactam antibiotics and their peptidoglycan analogues. We postulate that PknB-like kinases are key regulators of cell-wall biosynthesis. The essential function of these enzymes suggests an additional pathway for the action of β-lactam antibiotics.     

Cell death: a trigger of autoimmunity?

Systemic autoimmune diseases are characterized by the production of antibodies against a broad range of self-antigens. Recent evidence indicates that the majority of these autoantigens are modified in various ways during cell death. This has led to the hypothesis that the primary immune response in the development of autoimmunity is directed to components of the dying cell. In this article, we summarize data on the modification of autoantigens during cell death and the possible consequences of this for autoimmunity.     

A tale of two tails: why are terminal residues of proteins exposed?

MOTIVATION: It is widely known that terminal residues of proteins (i.e. the N- and C-termini) are predominantly located on the surface of proteins and exposed to the solvent. However, there is no good explanation as to the forces driving this phenomenon. The common explanation that terminal residues are charged, and charged residues prefer to be on the surface, cannot explain the magnitude of the phenomenon. Here, we survey a large number of proteins from the PDB in order to explore, quantitatively, this phenomenon, and then we use a lattice model to study the mechanisms involved. RESULTS: The location of the termini was examined for 425 small monomeric proteins (50-200 amino acids) and it was found that the average solvent accessibility of termini residues is 87.1% compared with 49.2% of charged residues and 35.9% of all residues. Using a cutoff of 50% of the maximal possible exposure, 80.3% of the N-terminal and 86.1% of the C-terminal residues are exposed compared to 32% for all residues. In addition, terminal residues are much more distant from the center of mass of their proteins than other residues. Using a 2D lattice, a large population of model proteins was studied on three levels: structural selection of compact structures, thermodynamic selection of conformations with a pronounced energy gap and kinetic selection of fast folding proteins using Monte-Carlo simulations. Progressively, each selection raises the proportion of proteins with termini on the surface, resulting in similar proportions to those observed for real proteins.     

The folding of single domain proteins--have we reached a consensus?

Rather than stressing the most recent advances in the field, this review highlights the fundamental topics where disagreement remains and where adequate experimental data are lacking. These topics include properties of the denatured state and the role of residual structure, the nature of the fundamental steps and barriers, the extent of pathway heterogeneity and non-native interactions, recent comparisons between theory and experiment, and finally, dynamical properties of the folding reaction.     

The GTP-binding domain of McrB: more than just a variation on a common theme?

The methylation-dependent restriction endonuclease McrBC from Escherichia coli K12 cleaves DNA containing two R(m)C dinucleotides separated by about 40 to 2000 base-pairs. McrBC is unique in that cleavage is totally dependent on GTP hydrolysis. McrB is the GTP binding and hydrolyzing subunit, whereas MrC stimulates its GTP hydrolysis. The C-terminal part of McrB contains the sequences characteristic for GTP-binding proteins, consisting of the GxxxxGK(S/T) motif (position 201-208), followed by the DxxG motif (position 300-303). The third motif (NKxD) is present only in a non-canonical form (NTAD 333-336). Here we report a mutational analysis of the putative GTP-binding domain of McrB. Amino acid substitutions were initially performed in the three proposed GTP-binding motifs. Whereas substitutions in motif 1 (P203V) and 2 (D300N) show the expected, albeit modest effects, mutation in the motif 3 is at variance with the expectations. Unlike the corresponding EF-Tu and ras -p21 variants, the D336N mutation in McrB does not change the nucleotide specificity from GTP to XTP, but results in a lack of GTPase stimulation by McrC. The finding that McrB is not a typical G protein motivated us to perform a search for similar sequences in DNA databases. Eight microbial sequences were found, mainly from unfinished sequencing projects, with highly conserved sequence blocks within a presumptive GTP-binding domain. From the five sequences showing the highest homology, 17 invariant charged or polar residues outside the classical three GTP-binding motifs were identified and subsequently exchanged to alanine. Several mutations specifically affect GTP affinity and/or GTPase activity. Our data allow us to conclude that McrB is not a typical member of the superfamily of GTP-binding proteins, but defines a new subfamily within the superfamily of GTP-binding proteins, together with similar prokaryotic proteins of as yet unidentified function.     

MUC genes: a superfamily of genes? Towards a functional classification of human apomucins

The MUC genes encode epithelial mucins. Eight different human genes have been well characterized, and two others identified more recently. Among them, a family of four genes, expressed in the respiratory and digestive tracts, is clustered to chromosome 11p15.5; and these genes encode gel-forming mucins which are structurally related to the superfamily of cystine-knot growth factors. A second group is composed of three independent genes encoding various isoforms of mucins including membrane-bound mucins associated to carcinomas. In this second group, MUC3 and MUC4 encode large apomucins containing EGF-like domains.     

Cloning and identifying of a novel protein binding with death domain of the death receptor 4

DR4 (Death Receptor 4) belongs to the tumor necrosis factor (TNF) receptor gene family, which is defined by similar, cysteine-rich extracellular domain and a homologous cytoplasmic sequence termed as "death domain". DR4 can transmit apoptosis signal initiated by Apo2L/TRAIL (TNF-related apoptosis inducing ligand). It can activate caspases within seconds of ligand binding and cause an apoptotic demise of the cell within hours. Despite several investigations, the mechanisms of apoptosis initiation by Apo2L/TRAIL remain unclear.     

The sterol-sensing domain: multiple families, a unique role?

The "sterol-sensing domain" (SSD) is conserved across phyla and is present in several membrane proteins, such as Patched (a Hedgehog receptor) and NPC-1 (the protein defective in Niemann-Pick type C1 disease). The role of the SSD is perhaps best understood from the standpoint of its involvement in cholesterol homeostasis. This article discusses how the SSD appears to function as a regulatory domain involved in linking vesicle trafficking and protein localization with such varied processes as cholesterol homeostasis, cell signalling and cytokinesis.     

The p66shc protein: a mediator of the programmed death of an organism?

Recently knockout of the gene encoding an adaptor protein (p66shc) was shown both to prolong the life span of an animal and to prevent apoptosis of cells in response to added H2O2 (Migliaccio et al. [1999] Nature 402, 309-313). A hypothesis is put forward in which p66shc is assumed to be involved in phenoptosis, i.e., programmed death of an organism, mediated by the reactive oxygen species-dependent massive apoptosis in an organ of vital importance. The reactive oxygen species are suggested to oxidize phosphatidyl serine in the inner leaflet of the cell plasma membrane, resulting in appearance of this phospholipid in the outer membrane leaflet, an effect recognized by a special receptor and causing the p66shc phosphorylation at a serine residue. Serine-phosphorylated p66shc there is proposed to block mitosis and initiate apoptosis. The large-scale apoptosis leads to phenoptosis and, hence, shortens the life span of the organism.     

The end of autophagic cell death?

In the mammalian system, cell death is often preceded or accompanied by autophagic vacuolization, a finding that initially led to the widespread belief that so-called "autophagic cell death" would be mediated by autophagy. Thanks to the availability of genetic tools to disable the autophagic machinery, it has become clear over recent years that autophagy usually constitutes a futile attempt of dying cells to adapt to lethal stress rather than a mechanism to execute a cell death program. Recently, we systematically addressed the question as to whether established or prospective anticancer agents may induce "autophagic cell death". Although a considerable portion among the 1,400 compounds that we evaluated induced autophagic puncta and actually increased autophagic flux, not a single one turned out to kill tumor cells through the induction of autophagy. Thus, knockdown of essential autophagy genes (such as ATG5 and ATG7) failed to prevent and rather accelerated chemotherapy-induced cell death, in spite of the fact that this manipulation efficiently inhibits autophagosome formation. Herein, we review these finding and--polemically--raise doubts as to the very existence of "autophagic cell death".     

Mitotic death: a mechanism of survival? A review

Mitotic death is a delayed response of p53 mutant tumours that are resistant to genotoxic damage. Questions surround why this response is so delayed and how its mechanisms serve a survival function. After uncoupling apoptosis from G1 and S phase arrests and adapting these checkpoints, p53 mutated tumour cells arrive at the G2 compartment where decisions regarding survival and death are made. Missed or insufficient DNA repair in G1 and S phases after severe genotoxic damage results in cells arriving in G2 with an accumulation of point mutations and chromosome breaks. Double strand breaks can be repaired by homologous recombination during G2 arrest. However, cells with excessive chromosome lesions either directly bypass the G2/M checkpoint, starting endocycles from G2 arrest, or are subsequently detected by the spindle checkpoint and present with the features of mitotic death. These complex features include apoptosis from metaphase and mitosis restitution, the latter of which can also facilitate transient endocycles, producing endopolyploid cells. The ability of cells to initiate endocycles during G2 arrest and mitosis restitution most likely reflects their similar molecular environments, with down-regulated mitosis promoting factor activity. Resulting endocycling cells have the ability to repair damaged DNA, and although mostly reproductively dead, in some cases give rise to mitotic progeny. We conclude that the features of mitotic death do not simply represent aberrations of dying cells but are indicative of a switch to amitotic modes of cell survival that may provide additional mechanisms of genotoxic resistance.     

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.