Structure and function of plasminogen/plasmin system

The main physiological function of plasmin is blood clot fibrinolysis and restoration of normal blood flow. To date, however, it became apparent that in addition to thrombolysis, the plasminogen/plasmin system plays an important physiological and pathological role in a number of other essential processes: degradation of the extracellular matrix, embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and tumor cell migration. This review focuses on structural features of plasminogen, regulation of its activation by physiological plasminogen activators, inhibitors of plasmin, and plasminogen activators, and the role of plasminogen binding to fibrin, cellular receptors, and extracellular ligands in various functions performed by plasmin thus formed.     

New insights into molecular structure and function of ecto-nucleotidases in the nervous system

Nucleotides can be released as signaling substances in the nervous system from both neural and glial cells. Their function is terminated by ecto-nucleotidases and sequential extracellular metabolism to the nucleoside. Recently considerable progress has been made in unraveling the molecular structure of an ecto-ATPase and an ecto-ATP diphosphohydrolase, two closely related ecto-enzymes. Molecular structure, tissue distribution and functional properties of the ecto-nucleotidases are discussed with particular emphasis on the nervous system. © 1998 Elsevier Science Ltd. All rights reserved.     

New insights into pectin methylesterase structure and function

In bacteria, fungi and plants, pectin methylesterases are ubiquitous enzymes that modify the degree of methylesterification of pectins, which are major components of plant cell walls. Such changes in pectin structure are associated with changes in cellular adhesion, plasticity, pH and ionic contents of the cell wall and influence plant development and stress responses. In plants, pectin methylesterases belong to large multigene families, are regulated in a highly specific manner, and are involved in vegetative and reproductive processes, including wood and pollen formation, in addition to plant-pathogen interactions. Although, overall, protein structures are highly conserved between isoforms, recent data indicate that structural variations might be associated with the targeting and functions of specific pectin methylesterases.     

New insights into the structure and function of potassium channels.

Potassium channels are surprisingly modular proteins. Well-defined regions that determine functional properties such as ion conduction and gating have recently been identified.     

New molecular insights into CETP structure and function: a review

Cholesteryl ester transfer protein (CETP) is important clinically and is the current target for new drug development. Its structure and mechanism of action has not been well understood. We have combined current new structural and functional methods to compare with relevant prior data. These analyses have led us to propose several steps in CETP's function at the molecular level, in the context of its interactions with lipoproteins, e.g., sensing, penetration, docking, selectivity, ternary complex formation, lipid transfer, and HDL dissociation. These new molecular insights improve our understanding of CETP's mechanisms of action.     

New insights into microtubule structure and function from the atomic model of tubulin

The structure of tubulin has recently been solved by electron crystallography of zinc-induced tubulin sheets. Because tubulin was studied in a polymerized state, the model contains information on the interactions between monomers that give rise to the αβ dimer as well as contacts between adjacent dimers that result in the structure of the protofilament. The model includes the binding site of taxol, an anti-cancer agent that acts by stabilizing microtubules. The present tubulin model gives the first structural framework for understanding microtubule polymerization and its regulation by nucleotides and anti-mitotic drugs at the molecular level. Received: 15 December 1997 / Revised version: 25 January 1998 / Accepted: 2 February 1998     

New insights into creatine function and synthesis

The text-book view of the role of the creatine/creatine phosphate system as an energy buffer has been expanded to include functions such as energy shuttling, proton buffering and regulating cytosolic ADP levels. There is continuous need for creatine replacement due to creatinine formation. Replacement involves a combination of diet and de novo synthesis. Creatine synthesis makes very significant demands on amino acid metabolism, in particular that of glycine, arginine and methionine. It uses about 40% of all methyl groups transferred from S-adenosylmethionine. Although the traditional view of the function of the creatine/creatine phosphate system is largely concerned with its role in skeletal and cardiac muscle, recent work obliges us to take a broader view. In particular, its role in the brain is brought into sharp focus by the neurological symptoms displayed by children suffering from inborn errors of creatine synthesis and transport, as well as by suggestions that brain creatine status may play a role in cognitive performance in adults.     

New insights into prion structure and toxicity

Prion diseases in humans and animals are due to conformational conversion of PrP(C), a cellular glycoprotein of unknown function, into PrP(Sc), an isoform that appears to be infectious in the absence of nucleic acids. Proteins that behave as prions are also found in yeast and filamentous fungi. Although there is now strong experimental support for the hypothesis that prions are infectious proteins, two subjects have remained poorly understood: the structure of prions, and the mechanisms by which they kill neurons. In this review, we will highlight recent studies that shed new light on these important issues.     

New insights into the function of Atg9

Autophagy is a lysosomal degradation pathway that is essential for cellular homeostasis. Identification of more than 30 autophagy related proteins including a multi-spanning membrane protein, Atg9, has increased our understanding of the molecular mechanisms involved in autophagy. Atg9 is required for autophagy in several eukaryotic organisms although its function is unknown. Recently, we identified a novel interacting partner of mAtg9, p38 MAPK interacting protein, p38IP. We summarise recent data on the role of Atg9 trafficking in yeast and mammalian autophagy and discuss the role of p38IP and p38 MAPK in regulation of mAtg9 trafficking and autophagy.     

Apolipoprotein E structure: insights into function

Human apolipoprotein E (apoE) is a member of the family of soluble apolipoproteins. Through its interaction with members of the low-density lipoprotein receptor family, apoE has a key role in lipid transport both in the plasma and in the central nervous system. Its three common structural isoforms differentially affect the risk of developing atherosclerosis and neurodegenerative disorders, including Alzheimer's disease. Because the function of apoE is dictated by its structure, understanding the structural properties of apoE and its isoforms is required both to determine its role in disease and for the development of therapeutic strategies.     

New insights into the emerging effects of inflammatory response on HDL particles structure and function

According to the increasing results, it has been well-demonstrated that the chronic inflammatory response, including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease are associated with an increased risk of atherosclerotic cardiovascular disease. The mechanism whereby inflammatory response up-regulates the risk of cardio-metabolic disorder disease is multifactorial; furthermore, the alterations in high density lipoprotein (HDL) structure and function which occur under the inflammatory response could play an important modulatory function. On the other hand, the serum concentrations of HDL cholesterol (HDL-C) have been shown to be reduced significantly under inflammatory status with remarked alterations in HDL particles. Nevertheless, the potential mechanism whereby the inflammatory response reduces serum HDL-C levels is not simply defined but reduces apolipoprotein A1 production. The alterations in HDL structure mediated by the inflammatory response has been also confirmed to decrease the ability of HDL particle to play an important role in reverse cholesterol transport and protect the LDL particles from oxidation. Recently, it has been shown that under the inflammatory condition, diverse alterations in HDL structure could be observed which lead to changes in HDL function. In the current review, the emerging effects of inflammatory response on HDL particles structure and function are well-summarized to elucidate the potential mechanism whereby different inflammatory status modulates the pathogenic development of dyslipidemia.

     

Microglia - insights into immune system structure, function, and reactivity in the central nervous system

Microglia are essential cellular components of a well-functioning central nervous system (CNS). The development and establishment of the microglial population differs from the other major cell populations in the CNS i.e. neurons and macroglia (astrocytes and oligodendrocytes). This different ontogeny gives microglia unique properties. In recent years detailed studies of the microglial population have been greatly facilitated by the use of bone marrow (BM) chimeric animals. Experimental BM transplants have provided the opportunity to trace and investigate how BM cells migrate into the CNS and settle to become microglia. Furthermore various functional properties of microglia in the normal and pathological CNS are now being revealed because of combinations of BM transplantations and experimental disease models. Here, we describe some of the latest findings in microglial biology and discuss the potential for using microglia in therapeutic interventions.     

New insights into the t-complex and control of sperm function

The mouse t-complex, located on chromosome 17, contains genes known to influence male, but not female, fertility. Although some t-complex genes are recessive lethals, t-chromosomes are maintained in the population by transmission ratio distortion. When male mice heterozygous for the t-chromosome mate with wild-type females, most offspring will possess the t-chromosome, indicating a link between t-complex genes and sperm function. Several proteins coded for by t-complex genes have been localised in the sperm flagellum, suggesting roles relating to motility. Another t-complex protein appears able to regulate the adenylyl cyclase/cAMP signal transduction pathway, known to play an important role in capacitation. Defective motility and/or failure to capacitate (“switch on”) would result in poorly fertile or infertile spermatozoa. Given the existence of human homologues for many genes in the t-complex and the prevalence of “male factor” infertility, information obtained about the t-complex not only will provide insight into basic biological mechanisms but may be of future clinical relevance as well. BioEssays 21:304–312, 1999. © 1999 John Wiley & Sons, Inc.     

New insights into plastid nucleoid structure and functionality

Investigations over many decades have revealed that nucleoids of higher plant plastids are highly dynamic with regard to their number, their structural organization and protein composition. Membrane attachment and environmental cues seem to determine the activity and functionality of the nucleoids and point to a highly regulated structure–function relationship. The heterogeneous composition and the many functions that are seemingly associated with the plastid nucleoids could be related to the high number of chromosomes per plastid. Recent proteomic studies have brought novel nucleoid-associated proteins into the spotlight and indicated that plastid nucleoids are an evolutionary hybrid possessing prokaryotic nucleoid features and eukaryotic (nuclear) chromatin components, several of which are dually targeted to the nucleus and chloroplasts. Future studies need to unravel if and how plastid–nucleus communication depends on nucleoid structure and plastid gene expression.     

Analysis of the kinesin superfamily: insights into structure and function

Kinesin superfamily proteins (KIFs) are key players or 'hub' proteins in the intracellular transport system, which is essential for cellular function and morphology. The KIF superfamily is also the first large protein family in mammals whose constituents have been completely identified and confirmed both in silico and in vivo. Numerous studies have revealed the structures and functions of individual family members; however, the relationships between members or a perspective of the whole superfamily structure until recently remained elusive. Here, we present a comprehensive summary based on a large, systematic phylogenetic analysis of the kinesin superfamily. All available sequences in public databases, including genomic information from all model organisms, were analyzed to yield the most complete phylogenetic kinesin tree thus far, comprising 14 families. This comprehensive classification builds on the recently proposed standardized nomenclature for kinesins and allows systematic analysis of the structural and functional relationships within the kinesin superfamily.     

Role of plasminogen, plasmin, and plasminogen activators in the migration of fibroblasts into plasma clots

Human diploid fibroblasts were seeded onto or into plasma clots and different aspects of cell adhesion and migration were measured. The roles of plasminogen activators and plasmin were studied by either the removal of plasminogen from plasma prior to clotting or by the addition of 10 mM epsilon-aminocaproic acid, which brings about an inhibition of plasmin in this system. When cells were seeded onto the surface of plasma clots, rates of attachment, spreading, and migration were unaffected by plasminogen depletion or plasmin inhibition. In contrast, when cells were seeded into plasma clots, then, although the rates of cells spreading were unaffected, cell migration was abolished by plasminogen depletion or by plasmin inhibition. When cells were seeded onto the surface of plasma clots and the rate of migration into the clots was measured, there was an absolute requirement for plasmin activity; while fibroblasts migrated rapidly into the fibrin lattice of control clots, in the case of plasminogen-depleted clots, cells failed to penetrate the lattice. Focussing through a plasma clot revealed that fibroblasts do not migrate through the fibrin lattice but instead, localized areas of fibrinolysis are generated and cells migrate over the surface of the area of lysis.