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PubMed1999

Association of neuronal calcium channels with modular adaptor proteins.

Presynaptic voltage-gated calcium (Ca(2+)) channels mediate Ca(2+) influx into the presynaptic terminal that triggers synaptic vesicle fusion and neurotransmitter release. The immediate proximity of Ca(2+) channels to the synaptic vesicle release apparatus is critical for rapid and efficient synaptic transmission. In a series of biochemical experiments, we demonstrate a specific association of the cytosolic carboxyl terminus of the N-type Ca(2+) channel pore-forming alpha(1B) subunit with the modular adaptor proteins Mint1 and CASK. The carboxyl termini of alpha(1B) bind to the first PDZ domain of Mint1 (Mint1-1). The proline-rich region present in the carboxyl termini of alpha(1B) binds to the SH3 domain of CASK. Mint1-1 is specific for the E/D-X-W-C/S-COOH consensus, which defines a novel class of PDZ domains (class III). The Mint1-1 PDZ domain-binding motif is present only in the "long" carboxyl-terminal splice variants of N-type (alpha(1B)) and P/Q-type (alpha(1A)) Ca(2+) channels, but not in R-type (alpha(1E)) or L-type (alpha(1C)) Ca(2+) channels. Our results directly link presynaptic Ca(2+) channels to a macromolecular complex formed by modular adaptor proteins at synaptic junction and advance our understanding of coupling between cell adhesion and synaptic vesicle exocytosis.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Modular structure of a docking surface on MAPK phosphatases.

Mitogen-activated protein kinases (MAPKs) must be precisely inactivated to achieve proper functions in the cells. Ten members of dual specificity phosphatases specifically acting on MAPKs, termed MAPK phosphatases (MKPs), have been reported. Each member has its own substrate specificity that should be tightly regulated. However, the molecular mechanism underlying the regulation of the specificity is largely unknown. In the MAPK signaling pathways, docking interactions, which are different from transient enzyme-substrate interaction, are known to regulate the enzymatic specificity. Here we have identified and characterized a docking surface of MKPs. Our results show that a docking surface is composed of a tandem alignment of three subregions (modules): a cluster of positively charged amino acids, a cluster of hydrophobic amino acids, and a cluster of positively charged amino acids (positive-hydrophobic-positive). This modular structure well fits the docking groove on MAPKs that we have previously identified and may contribute to regulating the docking specificity of the MKP family. The position, number, and species of charged amino acids in each module including the central hydrophobic subregion are important factors in regulation of docking to specific MAPKs. This modular structure in the docking interaction may define a novel model of protein-protein interaction that would also regulate other systems.

Amino Acid Sequence↗

PubMed2002

Modular arrangement and secretion of a multidomain serine protease. Evidence for involvement of proline-rich region and N-glycans in the secretion pathway.

The Limulus Factor C (FC), a multidomain glycoprotein that binds bacterial endotoxin with high affinity, belongs to the serine protease family of the complement and blood coagulation cascade. Here, we provide compelling evidence for the importance of modular arrangement and relevance of the proline-rich region (PRR) and N-glycosylation to the secretion and function of FC. We propose that PRR could be a universal conformational domain that regulates protein folding and targeting. FCs lacking PRR preceding the serine protease domain, were localized intracellularly. Misfolded conformers of the intracellular FCs were more susceptible to trypsin digestion. Glycosylation inhibition studies indicate that the presence but not the exact structure of the N-glycans affects the secretion of FC, although the complexity of glycosylation may influence its endotoxin-induced proteolytic cleavage with resultant enzymatic activity. Disruption of specific N-glycan sites at positions 740, 767, and 912, downstream of the PRR, at or near the serine protease domain, blocks its secretion. Co-expressed molecular chaperones like canine calnexin associates with glycosylated FCs to increase its solubility and secretion level but did not alter their expression profiles. Our results clearly demonstrate that the folding and secretion of a multidomain serine protease like FC are determined by its modular domain arrangement and site-specific N-glycans. The secreted FCs containing the N-terminal portion of FC are able to detect lipopolysaccharide with high sensitivity. We also identified the lectin-like and sushi 4 domains to contribute to the binding of lipopolysaccharide.

Amino Acid Sequence↗

PubMed1991

Neuroscience, modularity and personality theory: conceptual foundations of a model of complex human functioning.

The purpose of this paper is to lay the groundwork for the development of a scientific theory of complex human functioning. We first discuss the assumptions on which our thinking is based, then advance the argument that behavior, and human activity in general, may be more fully understood in light of current data on the structural organization of the central nervous system. The brain is organized as a modular, distributed, self-organizing system, which is in constant transaction with the environment. Because of its plasticity, structural and functional change occurs in the brain as a result of experience throughout life. It is our thesis that complex human behavior is organized in a similar manner - that is, human personality and behavior manifest themselves as modular systems. The insights provided by an understanding of the relationship of brain and behavior may enhance the capacity to explain both normal and pathological personality functioning.

Adaptation, Psychological↗

PubMed1995

On the modularity of face recognition: the riddle of domain specificity.

The present paper focuses on the modular attributes of face recognition, defined in terms of domain specificity. Domain specificity is examined by looking into the innate nature of face recognition, the special effects related to the recognition of inverted faces, the specificity of electrophysiological responsivity to facial stimuli, and the specific impairment in face recognition associated with localized brain damage. Converging evidence from these sources seems to consistently show that face recognition is not qualitatively unique, as it proceeds in a manner similar to the recognition of other visuospatial objects. However, it seems to be special in that it may involve specific mechanisms dedicated to face recognition. Among infants, differential responsivity to faces and to other objects in terms of age of onset, attraction and course of development, seems to indicate the operation of a special process. Unusual inversion effects in face recognition might be due to the special expertise that humans develop for recognizing upright faces. Face-selective single unit responses in the monkey's brain implies the existence in the visual system of cells which are exclusively dedicated to the processing of facial stimuli. Finally, in prosopagnosia localized brain damage is linked to a specific inability to recognize familiar faces. Taken together, the data seem to show that some elements in the process of face recognition are domain specific, and in that sense, modular.

Agnosia↗

PubMed1997

Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity.

SR proteins are required for constitutive pre-mRNA splicing and also regulate alternative splice site selection in a concentration-dependent manner. They have a modular structure that consists of one or two RNA-recognition motifs (RRMs) and a COOH-terminal arginine/serine-rich domain (RS domain). We have analyzed the role of the individual domains of these closely related proteins in cellular distribution, subnuclear localization, and regulation of alternative splicing in vivo. We observed striking differences in the localization signals present in several human SR proteins. In contrast to earlier studies of RS domains in the Drosophila suppressor-of-white-apricot (SWAP) and Transformer (Tra) alternative splicing factors, we found that the RS domain of SF2/ASF is neither necessary nor sufficient for targeting to the nuclear speckles. Although this RS domain is a nuclear localization signal, subnuclear targeting to the speckles requires at least two of the three constituent domains of SF2/ASF, which contain additive and redundant signals. In contrast, in two SR proteins that have a single RRM (SC35 and SRp20), the RS domain is both necessary and sufficient as a targeting signal to the speckles. We also show that RRM2 of SF2/ASF plays an important role in alternative splicing specificity: deletion of this domain results in a protein that, although active in alternative splicing, has altered specificity in 5' splice site selection. These results demonstrate the modularity of SR proteins and the importance of individual domains for their cellular localization and alternative splicing function in vivo.

Alternative Splicing↗

PubMed1997

The pneumococcal cell wall degrading enzymes: a modular design to create new lysins?

Autolysins are enzymes that degrade different bonds in the peptidoglycan and, eventually, cause the lysis and death of the cell. Streptococcus pneumoniae contains a powerful autolytic enzyme that has been characterized as an N-acetylmuramoyl-L-alanine amidase. We have cloned the lytA gene coding for this amidase and studied in depth the genetics and expression of this gene, which represented the first molecular analysis of a bacterial autolysin. Two observations have been fundamental in revealing further knowledge on the lytic systems of pneumococcus: (a) The well-documented dependence of the pneumococcal autolysin on the presence of choline in the cell wall for activity, and (b) the early observation that most pneumococcal phages also required the presence of this amino-alcohol in the growth medium to achieve a successful liberation of the phage progeny. We concluded that choline would serve as an element of strong selective pressure to preserve certain structures of the host and phage lytic enzymes which should lead to sequence homologies. We constructed active chimeras between the lytic enzymes of S. pneumoniae and its bacteriophages using genes that share sequence homology as well as genes that completely lack homologous regions. In this way, we demonstrated that the pneumococcal lytic enzymes are the result of the fusion of two independent functional modules where the carboxy-terminal domain might be responsible for the specific recognition of choline-containing cell walls whereas the active center of these enzymes should be localized in the N-terminal part of the protein. The modular design postulated for the pneumococcal lysins seems to be a widespread model for many types of microbial proteins and the construction of functional chimeric proteins between the lytic enzymes of pneumococcus and those of several gram-positive microorganisms, like Clostridium acetobutylicum or Lactococcus lactis, provided interesting clues on the modular evolution of proteins. The study of several genes coding for the lytic enzymes of temperate phages of pneumococcus also highlighted on some evolutionary relationships between microorganisms. We suggest that lysogenic relationships may represent a common mechanism by which pathogenic organisms like pneumococcus should undergo a rapid adaptation to an evolving environment.

Bacteriolysis↗

PubMed2002

Modular self-assembly of a Y-shaped multiprotein complex from seven nucleoporins.

Now that it is likely that all yeast nucleoporins are known, one of the ultimate goals is the in vitro assembly of the entire nuclear pore complex from its approximately 30 individual components. Here, we report the reconstitution of seven proteins (Nup133p, Nup145p-C, Nup120p, Nup85p, Nup84p, Seh1p and Sec13p) into a heptameric 0.5 MDa nuclear pore subcomplex. We found that double plasmid transformation combined with bi-cistronic mRNA translation allow the expression and assembly of distinct subcomplexes of up to five nucleoporins in a single Escherichia coli cell. During the sequential reconstitution of the Nup84p complex, smaller assembly intermediates can be isolated, which exhibit modular structures determined by electron microscopy that finally make up the whole Y-shaped Nup84p complex. Importantly, a seventh subunit, Nup133p, was incorporated into the complex through its interaction with Nup84p, thereby elongating one arm of the Y-shaped assembly to an approximately 40 nm long stalk. Taken together, our data document that the Nup84p-Nup133p complex self-assembles in a modular concept from distinct smaller nucleoporin construction sets.

Escherichia coli↗

PubMed1995

Modular structural elements in the replication origin region of Tetrahymena rDNA.

Computer analyses of the DNA replication origin region in the amplified rRNA genes of Tetrahymena thermophila identified a potential initiation zone in the 5'NTS [Dobbs, Shaiu and Benbow (1994), Nucleic Acids Res. 22, 2479-2489]. This region consists of a putative DNA unwinding element (DUE) aligned with predicted bent DNA segments, nuclear matrix or scaffold associated region (MAR/SAR) consensus sequences, and other common modular sequence elements previously shown to be clustered in eukaryotic chromosomal origin regions. In this study, two mung bean nuclease-hypersensitive sites in super-coiled plasmid DNA were localized within the major DUE-like element predicted by thermodynamic analyses. Three restriction fragments of the 5'NTS region predicted to contain bent DNA segments exhibited anomalous migration characteristic of bent DNA during electrophoresis on polyacrylamide gels. Restriction fragments containing the 5'NTS region bound Tetrahymena nuclear matrices in an in vitro binding assay, consistent with an association of the replication origin region with the nuclear matrix in vivo. The direct demonstration in a protozoan origin region of elements previously identified in Drosophila, chick and mammalian origin regions suggests that clusters of modular structural elements may be a conserved feature of eukaryotic chromosomal origins of replication.

Animals↗

PubMed1999

Srp2, an SR protein family member of fission yeast: in vivo characterization of its modular domains.

We isolated srp2, a gene encoding a protein composed of two RNA binding domains (RBDs) at the N-terminus followed by an arginine-rich region that is flanked by two short SR (serine/arginine) elements. The RBDs contain the signatures RDADDA and SWQDLKD found in RBD1 and RBD2 of all typical metazoan SR proteins. srp2 is essential for growth. We have analyzed in vivo the role of the modular domains of Srp2 by testing specific mutations in a conditional strain for complementation. We found that RBD2 is essential for function and determines the specificity of RBD1 in Srp2. Replacement of the first RBD with RBD1 of Srp1 of fission yeast does not change this specificity. The two SR elements in the C-terminus of Srp2 are also essential for function in vivo. Cellular distribution analysis with green fluorescence protein fused to portions of Srp2 revealed that the SR elements are necessary to target Srp2 to the nucleus. Furthermore, overexpression of modular domains of Srp2 and Srp1 show different effects on pre-mRNA splicing activity of the tfIId gene. Taken together, these findings are consistent with the notion that the RBDs of these proteins may be involved in pre-mRNA recognition.

Alleles↗

PubMed2000

Role of SR protein modular domains in alternative splicing specificity in vivo.

The SR proteins constitute a family of nuclear phosphoproteins which are required for constitutive splicing and also influence alternative splicing regulation. They have a modular structure consisting of one or two RNA recognition motifs (RRMs) and a C-terminal domain, rich in arginine and serine residues. The functional role of the different domains of SR proteins in constitutive splicing activity has been extensively studied in vitro; however, their contribution to alternative splicing specificity in vivo has not been clearly established. We sought to address how the modular domains of SR proteins contribute to alternative splicing specificity. The activity of a series of chimeric proteins consisting of domain swaps between different SR proteins showed that splice site selection is determined by the nature of the RRMs and that RRM2 of SF2/ASF has a dominant role and can confer specificity to a heterologous protein. In contrast, the identity of the RS domain is not important, as the RS domains are functionally interchangeable. The contribution of the RRMs to alternative splicing specificity in vivo suggests that sequence-specific RNA binding by SR proteins is required for this activity.

Adenovirus E1A Proteins↗

PubMed1999

Evolution of bHLH transcription factors: modular evolution by domain shuffling?

Multidomain proteins usually contain several conserved and apparently independently evolved domains. As a result, classifications based on only a single small domain may obscure the true evolutionary relationships of the proteins. The current classification of basic helix-loop-helix (bHLH) domain-containing proteins is based on the conserved bHLH domain alone. Herein, we explore whether sequence homology and, therefore, evolutionary relationships can be detected among the flanking or non-bHLH components of the amino acid sequences of 122 bHLH proteins. These 122 proteins were the same proteins previously used to construct the existing classification of the bHLH-domain-containing proteins. Several possible scenarios are examined in order to explain the observed patterns of sequence divergence, including (1) monophyly, (2) convergent evolution, (3) addition of functional components to the bHLH domain, and (4) modular evolution with domain shuffling. Drawing on several lines of evidence, we suggest that modular evolution by domain shuffling may have played an important role in the evolution of this large group of transcriptional regulators.

DNA-Binding Proteins↗

PubMed1997

Modular bifurcation endoprosthesis for treatment of abdominal aortic aneurysms.

OBJECTIVE: The authors analyzed a single group's experience treating abdominal aortic aneurysms (AAAs) with a new self-expanding, modular, bifurcated device. SUMMARY BACKGROUND DATA: Successful exclusion of AAAs by prototype devices has led to several controlled clinical trials evaluating prostheses designed and manufactured specifically for this application. METHODS: Sixteen patients (15 males, 1 female) of American Society of Anesthesiologists grade 2 through 4 and average age of 72 years had AAAs (average 57-mm diameter) treated as part of a phase I Food and Drug Administration-approved trial. RESULTS: All patients were treated successfully with no surgical conversions. No endoleaks or aneurysm enlargement was noted either predischarge by contrast computed tomography or on follow-up at 1 month by duplex ultrasound examination. At 6 months, 12 of 13 patients who were observed for this interval had no endoleaks, whereas one patient (patient 3) showed a small area of extravasation that appeared to arise from the device in an area that was traumatized at the time of deployment. One procedure-related mortality (6%) occurred in a patient who died of septic complications secondary to a gangrenous gallbladder diagnosed 1 day after the procedure. There were no device-related mortalities. Complications included two iliac artery dissections, two groin wound infections, and two transient elevations of serum creatinine. Other significant variables including median procedure length (5 hours), intensive care unit stay (1 day), hospitalization postprocedure (4.5 days), and blood loss (1100 mL) all decreased as the study progressed. Blood replacement in all but three patients was accomplished by autotransfusion or banked-autologous blood replacement. At 6-month follow-up in 13 patients, the maximum diameter of the aneurysm decreased by an average of 5.6 mm (range, 0-15 mm), and the maximal cross-sectional area decreased an average of 20.3% (range, 0-72%). CONCLUSIONS: This study suggests that endovascular prosthesis exclusion of AAAs using a self-expanding modular device may be effective in many patients who are otherwise surgical candidates for repair if further clinical studies confirm these observations.

Aged↗

PubMed1994

Modular activation and suppression of neocortical activity in the monkey revealed by optical imaging.

To examine functional local connections in the primate neocortex, we examined changes in optical signal by intracortical microstimulation (ICMS), using a voltage-sensitive dye (RH795) in frontal and parietal cortical areas of the anesthetized monkey. ICMS increased the optical signal at the stimulated site, followed by increases and decreases in a modular fashion at regions that were from hundreds of micrometres to a few millimetres from the stimulated site. These changes lasted for 100-250 ms after the offset of ICMS. Further, this increase in the optical signal was accompanied by an increase in electrical activity in the neurones. These findings suggest the presence of excitatory and inhibitory modular connections within the neocortical areas. It is likely that some functional 'modules' are activated concurrently by excitatory loops, which suppress the activity of other modules.

Animals↗

PubMed1996

Modular tibial augmentations in total knee arthroplasty.

Proximal tibial bony deficiencies are not uncommon in primary and revision total knee arthroplasty. Modular tibial augmentations were introduced to address these deficiencies. Alterations in strain distribution as a result of medial wedge and block augmentations were evaluated for a modular total knee arthroplasty system in 6 fresh frozen anatomic specimen tibias. Full-field strain patterns were examined using photoelastic coating methods, and high strain regions were evaluated using strain gage rosette techniques. The total knee arthroplasty installations were tested in static physiologic axial and torsional load configurations. The relative effects of sequential wedge and block augmentations compared with the nonaugmented case were statistically analyzed. There were no overall statistical differences in the 3 treatments in terms of maximal (principal) strains. A secondary analysis that evaluated specific location and load pattern combinations established several minor statistical differences along with insights into the manner in which each construct loads the proximal tibia. Although metal wedge augmentation commonly is used, block augmentation seems to be an appropriate alternative from a strain distribution standpoint in cases in which the block geometry better approximates the bony defect.

Bone Diseases↗

PubMed1996

Cobalt chromium molybdenum metal combination for modular hip prostheses.

The development of a metal combination for modular hip systems was motivated by the following observations: (1) wear particles from polyethylene acetabular components can lead to a foreign body reaction and late aseptic loosening and (2) well designed all metal hip prostheses had very low wear rates, usually causing no osteolytic problems. The following challenges had to be met: (1) metal alloy with the maximum wear resistance; (2) the optimal clearance (difference in diameter) between 28-mm ball head and acetabular component; and (3) equipping modern, modular hip systems with metal combinations while maintaining compatibility with existing components. The realization of a metal combination consisted of the stable anchoring of a standard metal lining in a polyethylene insert that, combined, is intended to provide adequate load transfer and fit to either the bone cement bed or the titanium shell. The metal lining is manufactured from a carbide containing cobalt chromium molybdenum wrought alloy (Protasul-21WF). From 1988 to 1995, approximately 40,000 metal combinations (Metasul) were implanted. From these, 44 single components, with a maximum time in situ of 5.5 years, were retrieved and examined. The total linear wear rate averaged 2 to 5 micrometers per year per component after the initial conditioning phase. Under these conditions, particle induced late aseptic loosening is not to be expected.

Biomechanical Phenomena↗

PubMed2001

Modular, mobile-bearing hinge total knee arthroplasty.

Early reports of hinge total knee arthroplasty showed high rates of complications and implant failure. Third-generation modular, mobile-bearing, hinge knee arthroplasty systems have evolved to decrease the deleterious stresses that contributed to the failures of earlier designs. The combined series of Barrack et al and Jones et al documents midterm results using the S-ROM Hinge Knee System for patients with significant soft and hard tissue deficiencies not suitable for standard, less constrained, revision knee systems. The combined series included 30 knees with a mean followup of 49 months. Knee Society clinical scores improved from 52 to 134 points. There were no mechanical failures of the implants. The knee system used provides press-fit diaphyseal stems and metaphyseal filling and loading sleeves, all of which showed apposition and positive remodeling of bone at followup radiographic analysis. The excellent midterm results of this modular, mobile-bearing, linked knee system suggest the orthopaedic surgeon can display increasing confidence in the selection of such a knee system when confronted with catastrophic, salvage knee arthroplasty.

Arthroplasty, Replacement, Knee↗

PubMed1991

Modular indirect calorimeter suitable for long-term measurements in multipatient intensive care units.

OBJECTIVE: The construction of an indirect calorimeter capable of long-term automated sequential monitoring of multiple patients in adult and pediatric ICUs. DESIGN: A prototype system utilizing modular engineering principles, including central respiratory mass spectrometer; validation by organic solvent combustion and nitrogen dilution methods, and Tissot spirometer. SETTING: Surgical and pediatric ICUs in a tertiary care university hospital. RESULTS: When expired minute volume was measured over a range of 4 to 28 L in six intubated patients, expired minute volume measured by the prototype system demonstrated a correlation coefficient of .998 compared with simultaneous expired minute volume measured by a Tissot spirometer. Organic solvent combustion demonstrated a maximum error of 3.8% for oxygen consumption (VO2) and an average error of 1.73 +/- 1.25% (SEM). The maximum error for the respiratory quotient was 3.0%, with an average error of 1.75 +/- 1.07%. VO2 (predicted) vs. VO2 (measured) demonstrated a correlation coefficient of .997. Validation with the nitrogen dilution method over a range of FIO2 from 0.21 to 0.60 demonstrated a maximum error of 7.9%, with an average error of -1.72 +/- 1.1% (n = 51). CONCLUSIONS: Indirect calorimetry by means of a shared system for measurements in multiple patients in ICUs is feasible and cost effective utilizing modular principles and a centralized respiratory gas analyzer.

Adult↗