The notion that all protein functions are determined through macromolecular interactions is the driving force behind current efforts that aim to solve the structures of all cellular complexes. Recent findings, however, demonstrate a significant amount of structural disorder or polymorphism in protein complexes, a phenomenon that has been largely overlooked thus far. It is our view that such disorder can be classified into four mechanistic categories, covering a continuous spectrum of structural states from static to dynamic disorder and from segmental to full disorder. To emphasize its generality and importance, we suggest a generic term, ‘fuzziness’, for this phenomenon. Given the crucial role of protein disorder in protein–protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome.
Mature miRNAs are 19–24 nucleotide noncoding RNAs that post-transcriptionally regulate gene expression in living cells by mediating targeted hydrolysis and translation inhibition of mRNAs. In recent years, miRNAs have been detected in a variety of biological fluids as extracellular nuclease-resistant entities. Importantly, extracellular circulating miRNAs are aberrantly expressed in blood plasma or serum during the course of many diseases, including cancer, and are promising noninvasive biomarkers. However, the biological function of extracellular miRNAs remains questionable. In this article, we summarise the current theories regarding extracellular miRNA origin and function, and suggest that these miRNAs are mostly byproducts of cellular activity. Nevertheless, some extracellular miRNA species might also carry cell–cell signaling function.
Several theories have proposed possible functions of adult neurogenesis in learning processes on a systems level, such as the avoidance of catastrophic interference and the encoding of temporal and contextual information, and in emotional behavior. Under the assumption of such functionality of new neurons, the question arises: what are the consequences of adult hippocampal neurogenesis beyond the temporally immediate computational benefit? What might provide the evolutionary advantage of maintaining neurogenesis in the dentate gyrus but almost nowhere else? I propose that over the course of life, activity-dependently regulated adult neurogenesis reveals its true significance in the retained ability for lasting and cumulative network adaptations. The hippocampal precursor cells that generate new neurons with their particular acute function represent a ‘neurogenic reserve’: the potential to remain flexible and plastic in hippocampal learning when the individual is exposed to novelty and complexity.
Carbonic anhydrase isoform IX (CA IX) is highly overexpressed in many types of cancer. Its expression, which is regulated by the HIF-1 transcription factor, is strongly induced by hypoxia and correlates with a poor response to classical chemo- and radiotherapies. CA IX contributes to acidification of the tumor environment by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons, thereby leading to acquisition of metastasic phenotypes and chemoresistance to weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific inhibitors, such as the sulfonamide indisulam, reverts these processes, establishing a clear-cut role for CA IX in tumorigenesis. Thus, selective CA IX inhibitors could prove useful for elucidating the role of CA IX in hypoxic cancers, for controlling the pH imbalance in tumor cells and for developing diagnostic or therapeutic applications for tumor management. Indeed, fluorescent inhibitors and membrane-impermeant sulfonamides have recently been used as proof-of-concept tools, demonstrating that CA IX is an interesting target for anticancer drug development.
Three originally distinct concepts – lipid rafts, detergent-resistant membranes (DRMs) and liquid-ordered (lo) lipid phases – are often confused in current literature; many researchers have assumed that all three names refer to the same chemico-biological entity. In fact, theoretical and experimental findings provide strong evidence against identifying DRMs with rafts and lo domains. Because much of what we think we know about lipid rafts is based on their unjustified identification as DRMs, functional domains in biological membranes might differ markedly from the generally accepted picture.
Allosteric drugs are increasingly used because they produce fewer side effects. Allosteric signal propagation does not stop at the ‘end’ of a protein, but may be dynamically transmitted across the cell. We propose here that the concept of allosteric drugs can be broadened to ‘allo-network drugs’ – whose effects can propagate either within a protein, or across several proteins, to enhance or inhibit specific interactions along a pathway. We posit that current allosteric drugs are a special case of allo-network drugs, and suggest that allo-network drugs can achieve specific, limited changes at the systems level, and in this way can achieve fewer side effects and lower toxicity. Finally, we propose steps and methods to identify allo-network drug targets and sites that outline a new paradigm in systems-based drug design.
The pursuit for drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. The first-generation inhibitors, Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modest activity. Several second-generation inhibitors are now in clinical trials. Future approaches to determine clinical benefit need to incorporate both the lessons learned from these early compounds and information recently obtained from the genetic analysis of CDKs in preclinical models. Here we discuss key concepts that should be considered when validating the clinical utility of CDK inhibitors in cancer therapy.
Multidrug and toxic compound extrusion (MATE) proteins, comprising the most recently designated family of multidrug transporter proteins, are widely distributed in all kingdoms of living organisms, although their function is far from understood. The bacterial MATE-type transporters that have been characterized function as exporters of cationic drugs, such as norfloxacin and ethidium, through H or Na exchange. Plant MATE-type transporters are involved in the detoxification of secondary metabolites, including alkaloids. Mammalian MATE-type transporters are responsible for the final step in the excretion of metabolic waste and xenobiotic organic cations in the kidney and liver through electroneutral exchange of H . Thus, we propose that members of the MATE family are organic cation exporters that excrete metabolic or xenobiotic organic cations from the body.
One of the most distinguishing features of the adult human brain is the complexity and diversity of its cortical astrocytes. Human protoplasmic astrocytes manifest a threefold larger diameter and have tenfold more primary processes than those of rodents. In all mammals, protoplasmic astrocytes are organized into spatially non-overlapping domains that encompass both neurons and vasculature. Yet unique to humans and primates are additional populations of layer 1 interlaminar astrocytes that extend long (millimeter) fibers, and layer 5–6 polarized astrocytes that also project distinctive long processes. We propose that human cortical evolution has been accompanied by increasing complexity in the form and function of astrocytes, which reflects an expansion of their functional roles in synaptic modulation and cortical circuitry.
Cdc48 (p97), a conserved chaperone-like ATPase of eukaryotic cells, has attracted attention recently because of its wide range of cellular functions. Cdc48 is intimately linked to the ubiquitin pathway because its primary action is to segregate ubiquitinated substrates from unmodified partners. This ‘segregase’ activity is crucial for certain proteasomal degradation pathways and for some nonproteolytic functions of ubiquitin. Cdc48 associates not only with different ‘substrate-recruiting cofactors’ but also with distinct ‘substrate-processing cofactors’. The latter proteins control the degree of ubiquitination of bound substrates by shifting the polyubiquitination reaction into ‘forward’, ‘neutral’ or ‘reverse’. We discuss how Cdc48 might use this ‘gearbox activity’ to control protein fate and propose a similar mode of action for the 19S cap of the proteasome.