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PubMed2000

The complementary brain: unifying brain dynamics and modularity.

How are our brains functionally organized to achieve adaptive behavior in a changing world? This article presents one alternative to the computer analogy that suggests brains are organized into independent modules. Evidence is reviewed that brains are in fact organized into parallel processing streams with complementary properties. Hierarchical interactions within each stream and parallel interactions between streams create coherent behavioral representations that overcome the complementary deficiencies of each stream and support unitary conscious experiences. This perspective suggests how brain design reflects the organization of the physical world with which brains interact. Examples from perception, learning, cognition and action are described, and theoretical concepts and mechanisms by which complementarity might be accomplished are presented.

Journal Article↗
PubMed2002

Modular motor learning.

An interesting theory of sensorimotor control has been recently extended and simulated. The simulation can learn to control an arm in several mutually exclusive 'contexts', situations where the arm carries one of four objects with different mechanical properties. It provides a good theoretical framework for testing biological motor systems.

Journal Article↗
PubMed2000

Modular evolution of the purine biosynthetic pathway.

Structural studies, sequence alignments, and biochemistry have provided new insights into the evolution of the purine biosynthetic pathway. The importance of chemistry, the binding of ribose 5-phosphate (common to all purine biosynthetic intermediates), and transient protein-protein interactions in channeling of chemically unstable intermediates have all been examined in the past few years.

Evolution, Molecular↗
PubMed2003

A two-component modular approach for enhancing T-cell activation utilizing a unique anti-FcgammaRI-streptavidin construct and microspheres coated with biotinylated-antigen.

The professional antigen presenting cell (APC) plays an essential role in the initiation and propagation of the acquired immune response. Thus, much work has been done in designing strategies that target vaccine antigen (Ag) to APC. Utilizing recombinant DNA technology, we have created a unique two-component system that delivers biotinylated Ag to the Fc gamma receptor type I (FcgammaRI) on APC. Our studies demonstrate that we can successfully engineer FcgammaRI-specific targeting element proteins that simultaneously bind both biotin and recognize FcgammaRI. Additionally, we are able to engineer biotinylated Ag, which form functional elements when adsorbed onto latex microspheres. Furthermore, the targeting and functional element components bind to each other and successfully form two-component immunogens. T-cell activation in response to targeted Ag-laden microspheres is 10- to 100-fold greater than the response to the non-targeted Ag-laden microspheres. This enhancement is 100- to 1000-fold greater than the responses generated to soluble Ag. Thus, our results suggest that specific targeting of Ag-laden microspheres to FcgammaRI may significantly enhance the adjuvant properties of microparticulate delivery systems. Further development of this system may help to elucidate the mechanisms involved in generating enhanced responses to APC-targeted vaccines and significantly advance vaccine technology.

Antigen-Presenting Cells↗
PubMed1990

Cortical connections of MT in four species of primates: areal, modular, and retinotopic patterns.

Cortical connections were investigated by restricting injections of WGA-HRP to different parts of the middle temporal visual area, MT, in squirrel monkeys, owl monkeys, marmosets, and galagos. Cortex was flattened and sectioned tangentially to facilitate an analysis of the areal patterns of connections. In the experimental cases, brain sections reacted for cytochrome oxidase (CO) or stained for myelin were used to delimit visual areas of occipital and temporal cortex and visuomotor areas of the frontal lobe. Major findings are as follows: (1) The architectonic analysis suggests that in addition to the commonly recognized visual fields, area 17 (V-I), area 18 (V-II), and MT, all three New World monkeys and prosimian galagos have visual areas DL, DI, DM, MST, and FST. (2) Measurements of the size of these areas indicate that about a third of the neocortex in these primates is occupied by the eight visual areas, but they occupy a somewhat larger proportion of neocortex in the diurnal marmosets and squirrel monkeys than the nocturnal owl monkeys and galagos. The diurnal primates also have proportionally more neocortex devoted to areas 17, 18, and DL and less to MT. These differences are compatible with the view that diurnal primates are more specialized for detailed object and color vision. (3) In all four primates, restricted locations in MT receive major inputs from short meandering rows of neurons in area 17 and several bands of neurons in area 18. (4) Major feedforward projections of MT are to two visual areas adjoining the rostral half of MT, areas MST and FST. Other ipsilateral connections are with DL, DI, and in some cases DM, parts of inferotemporal (IT) cortex, and posterior parietal cortex. (5) In squirrel monkeys, where injection sites varied from caudal to rostral MT, caudal parts of MT representing central vision connect more densely to DL and IT than other parts. Both DL and IT cortex emphasize central vision. (6) In the frontal lobe, MT has dense connections with the frontal ventral area (FV), but not with the frontal eye field (FEF). (7) Callosal connections of MT are most dense with matched locations in MT of the other hemisphere, rather than with the outer boundary of MT representing the vertical meridian. Targets of sparser callosal connections include FST, MST, and DL.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

Modular chemistry: secondary building units as a basis for the design of highly porous and robust metal-organic carboxylate frameworks.

Secondary building units (SBUs) are molecular complexes and cluster entities in which ligand coordination modes and metal coordination environments can be utilized in the transformation of these fragments into extended porous networks using polytopic linkers (1,4-benzenedicarboxylate, 1,3,5,7-adamantanetetracarboxylate, etc.). Consideration of the geometric and chemical attributes of the SBUs and linkers leads to prediction of the framework topology, and in turn to the design and synthesis of a new class of porous materials with robust structures and high porosity.

Carboxylic Acids↗
PubMed2007

Modular and dynamic functionalization of polymeric scaffolds.

The design and synthesis of multifunctionalized, architecturally controlled polymers is a prerequisite for a variety of future applications of polymeric materials. On the basis of Nature's use of self-assembly in the creation of biomaterials, this Account describes concepts that were developed over the past 5 years that utilize noncovalent interactions such as hydrogen bonding, ionic interactions, electrostatic interactions, metal coordination, and pi-pi stacking in modification of copolymer side-chains to obtain multifunctional polymeric materials, induce polymer morphology changes, and influence bulk-polymer properties.

Models, Theoretical↗
PubMed2004

Metal-assembled modular proteins: toward functional protein design.

Metal-assembled parallel helix-bundle proteins have been used to investigate electron transfer through alpha-helical structures. Fermi Golden Rule distance dependence of electron transfer rates was established in a family of designed metalloproteins, and the contribution of intrahelical hydrogen bonding to the matrix tunneling element was explored. The first steps toward the design of functional proteins using dynamic combinatorial assembly of alpha-helical structural elements are described.

Amino Acid Sequence↗
PubMed2002

From mechanistic studies on artemisinin derivatives to new modular antimalarial drugs.

In the first part of this account, the antimalarial drug artemisinin is presented, and the current hypotheses on the mechanism of action of this endoperoxide-based drug are reviewed. The alkylating ability of artemisinin and synthetic analogues toward heme related to their antimalarial efficacy are underlined. Some possible ways for discovery of new drugs, especially the design of trioxaquines, new active molecules recently patented that have been prepared by covalent attachment of a trioxane residue having alkylating ability to a quinoline moiety known to easily penetrate within infected erythrocytes, are presented.

Alkylating Agents↗
PubMedDate not supplied

A modular approach to the synthesis of new reagents useful in the chemical synthesis of modified DNA probes: derivatives of 3-(tert-butyldimethylsiloxy)glutaric anhydride as versatile building blocks in the synthesis of new phosphoramidites and modified solid supports.

We present a flexible and cost-efficient synthetic strategy for the preparation of a new family of phosphoramidite and solid-support reagents that can introduce a broad range of modifications into DNA probes. The key intermediate material 3 is synthesized using the inexpensive and commercially available 3-(tert-butyldimethylsiloxy)glutaric anhydride 1 and can be used as common starting material for the preparation of new labeling reagents.

Anhydrides↗
PubMed1993

Modularity of protein function: chimeric interleukin 1 beta s containing specific protease inhibitor loops retain function of both molecules.

Although it is widely recognized that many proteins contain discrete functional domains, it is less certain whether smaller, less obviously discrete, units of structure will retain their specific function when transplanted into a different context. The observation that the potent inflammatory cytokine human interleukin 1 beta has the same overall structure as soybean trypsin inhibitor (STI) (Kunitz) prompted us to replace a tight turn in the cytokine sequence with the large loop in soybean trypsin inhibitor that binds to the active site of trypsin. Wild-type interleukin 1 beta (IL-1 beta) is highly resistant to proteolysis, but the chimeric STI/IL is specifically cleaved by trypsin, apparently in the inserted loop. Other chimeric interleukins have also been constructed, by replacing the same tight turn with inhibitory loops from other protein protease inhibitors: turkey ovomucoid inhibitor (TOI), a chymotrypsin inhibitor, and alpha 1-antitrypsin (AT), an elastase inhibitor. Although these loops come from proteins not related structurally to interleukin 1, they confer specific protease sensitivity or inhibition on the chimeric cytokine. The cytokine properties of these chimeric interleukins have also been evaluated. The chimeras formed from human IL-1 beta and all inhibitory loops tested bind to the interleukin 1 receptor with reasonable affinity. The typical cellular effects of IL-1, however, are not observed with all the recombinant proteins, thus confirming that receptor binding and signal transduction can be uncoupled. When these results are taken together with the results of site-directed mutagenesis of IL-1, reported in this paper and elsewhere, they allow the receptor and intracellular transduction sites on the protein to be mapped in detail.

Amino Acid Sequence↗
PubMed1992

Modular mutagenesis of exons 1, 2, and 8 of a glutathione S-transferase from the mu class. Mechanistic and structural consequences for chimeras of isoenzyme 3-3.

Exons 1 and 2 and exon 8 of the mu class GSH transferases from rat encode sequence-variable regions 1 and 4 of mu class isoenzymes, respectively. These two of four variable regions are located at the N- and C-termini of this isoenzyme class and impinge on the active site. In order to assess the influence of these variable regions on the catalytic diversity of the class mu isoenzymes, seven chimeric isoenzymes were constructed by transplantation of the variable regions of the sequence of the type 4 subunit into the corresponding regions of the type 3 subunit. The chimeric isoenzymes exhibit unique catalytic properties. Replacement of all, or part, of variable region 4 of the type 3 subunit with that of the type 4 subunit results in chimeric catalysts with higher turnover numbers in nucleophilic aromatic substitution reactions. Analysis of the crystal structure of isoenzyme 3-3 [Ji, X., Zhang, P., Armstrong, R. N., & Gilliland, G. L. (1992) Biochemistry (preceding paper in this issue)] suggests that interaction of the flexible C-terminal tail with the N-terminal domain helps limit the rate of product release from the active site of isoenzyme 3-3 in this type of reaction. Substitution of all, or part, of the sequence-variable region 1 of subunit 3 with that of subunit 4 results in chimeric isoenzymes that mimic the high stereoselectivity but not the catalytic efficiency of isoenzyme 4-4 toward alpha,beta-unsaturated ketones.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Tissue-type plasminogen activator domain-deletion mutant BM 06.022: modular stability, inhibitor binding, and activation cleavage.

Recombinant BM 06.022 (M(r) 39,589) is a domain-deletion mutant of the human tissue-type plasminogen activator (tPA) structured by the kringle 2 and protease modules. Unfolding under various conditions was investigated via 1H-NMR spectroscopy by monitoring the well-resolved high-field methyl resonances at approximately -0.97 ppm (kringle 2) and approximately -0.29 and -0.54 ppm (protease). Reversible acid/base unfolding is manifest under low pH (< 4.8) conditions. It is observed that, relative to the protease, the kringle exhibits higher overall stability at low pH. At pH 4.6, BM 06.022 undergoes two distinct thermal melting transitions, at approximately 334 and approximately 352 K, assigned to an irreversible denaturation of the protease and a reversible unfolding of the kringle 2, respectively. Under the same conditions, the protease reacted with the active site inhibitor 1,5 dansyl-L-glutamylglycyl-L-arginine chloromethyl ketone (EGRck) exhibits a higher (approximately 10 K) thermal stability than the inhibitor-free protease. Upon acidification, the EGRck-modified protease unfolds irreversibly around pH 3.4. As exemplified by BM 06.022, a single-chain protein, as defined by continuity of the polypeptide backbone, can exhibit simultaneous folding reversibility and irreversibility for autonomous segments of the sequence. Conversion of the isolated (single-chain) protease or intact BM 06.022 to their catalytically active two-chain forms via plasminolytic cleavage of the Arg275-Ile276 peptide bond leaves the kringle 2 spectrum unaffected while perturbing the resolved high-field methyl resonances stemming from the protease. The latter also shift when the protease is reacted with EGRck, indicating that these signals are sensitive to events at the binding pocket.(ABSTRACT TRUNCATED AT 250 WORDS)

Acids↗
PubMed2002

An unexpected interaction between the modular polyketide synthases, erythromycin DEBS1 and pikromycin PikAIV, leads to efficient triketide lactone synthesis.

An unusual feature of the 6-module pikromycin polyketide synthase (PikPKS, PikAI-PikAIV) of S. venezuelae is the ability to generate both 12- and 14-membered ring macrolides. The PikAIV component containing the last extension module and a thioesterase domain is responsible for generating both of these products. In the case of the 12-membered ring macrolide, an acyl-enzyme intermediate on PikAIII is able to efficiently "skip" the last extension step and is cyclized by the TE domain of PikAIV, presumably as a result of a PikAIII-PikAIV interaction. Herein we report that plasmid-based expression (pBK3) of DEBS1, which comprises the loading domain and the first two modules of the Saccharopolyspora erythrea 6-deoxyerythronolide B synthase, in S. venezuelae leads to efficient 15 +/- 3 mg/L production of triketide lactone products (TKLs). Comparable levels of TKLs were observed with a plasmid (pBK1) which expressed DEBS1 fused to a TE domain (DEBS1-TE). These results are in stark contrast to previous in vivo and in vitro analyses, where only DEBS1-TE efficiently produces TKLs. Levels of TKLs decreased dramatically with expression of DEBS1 in both pikAIV and pikAIII-pikAIV deletion hosts (0.5 mg/L), but not DEBS1-TE, and could be partially restored by addition of a PikAIV complementation plasmid. These data suggest that PikAIV is able to efficiently catalyze formation of 6-membered lactone ring products from acyl-bound intermediates on DEBS1 in a manner analogous to that observed for 12-membered macrolide products from PikAIII. Significant sequence similarity and length of the C-terminal linker region of PikAIII and DEBS1 suggest that this region may be responsible for the interaction with PikAIV. A replacement of this linker region of DEBS1 with the corresponding region of PikAI led to a 95% decrease in TKL levels in S. venezuelae, consistent with this hypothesis.

Amino Acid Sequence↗
PubMed2005

The procapsid binding domain of phi29 packaging RNA has a modular architecture and requires 2'-hydroxyl groups in packaging RNA interaction.

The phi29 packaging RNA (pRNA) is an essential component in the phi29 bacteriophage DNA packaging motor, the strongest biomolecular motor known today. Utilizing Mg2+-dependent intermolecular base pairing interactions between two 4-nucleotide loops within the pRNA procapsid binding domain, multiple copies of pRNA form a ring-shaped complex that is indispensable for packaging motor function. To understand pRNA structural organization and pRNA/pRNA interaction, studies were carried out on pRNA closed dimers, the simplest functional pRNA complex believed to be the building blocks for assembling the oligomeric ring. Tertiary folding and interactions in various pRNA mutants were evaluated based on measured closed dimer affinity that is directly linked to the proper positioning of the interacting loops. The data revealed that the procapsid binding domain contains two autonomous modules that are capable of interacting noncovalently to form a fully active species in pRNA/pRNA interaction. Deleting the 2'-hydroxyl groups in one of the interacting loops weakens the dimer affinity by 125-fold, suggesting potential tertiary interactions involving these 2'-hydroxyl groups. The results provide evidence that nonbase functional groups are involved in pRNA folding and interaction and lead to a simple model that describes the pRNA monomer configuration in terms of three arms spanning a hinge. The functional constructs developed here will aid biophysical and biochemical investigations of pRNA structure and function, as well as developments of pRNA-based technology for nanoscience and gene therapy.

Bacillus Phages↗
PubMed2004

Reconstituting modular activity from separated domains of 6-deoxyerythronolide B synthase.

The hallmark of a type I polyketide synthase (PKS), such as the 6-deoxyerythronolide B synthase (DEBS), is the presence of catalytic modules comprised of covalently fused domains acting together to catalyze one round of chain elongation. In addition to an obligate ketosynthase (KS), acyl transferase (AT), and acyl carrier protein (ACP), a module may also include a ketoreductase (KR), dehydratase (DH), and/or enoyl reductase (ER) domain. The size, flexibility, and fixed domain-domain stoichiometry of these PKS modules present challenges for structural, mechanistic, and protein-engineering studies. Here, we have harnessed the power of limited proteolysis and heterologous protein expression to isolate and characterize individual domains of module 3 of DEBS, a 150-kD protein consisting of a KS, an AT, an ACP, and an inactive KR domain. Two interdomain boundaries were identified via limited proteolysis, which led to the production of a 90-kD KS-AT, a 142-kD KS-AT-KR(0), and a 10-kD ACP as structurally stable stand-alone proteins. Each protein was shown to possess the requisite catalytic properties. In the presence of the ACP, both the KS-AT and the KS-AT-KR(0) proteins were able to catalyze chain elongation as well as the intact parent module. Separation of the KS from the ACP enabled direct interrogation of the KS specificity for both the nucleophilic substrate and the partner ACP. Malonyl and methylmalonyl extender units were found to be equivalent substrates for chain elongation. Whereas ACP2 and ACP4 of DEBS could be exchanged for ACP3, ACP6 was a substantially poorer partner for the KS. Remarkably, the newly identified proteolytic sites were conserved in many PKS modules, raising the prospect of developing improved methods for the construction of hybrid PKS modules by engineering domain fusions at these interdomain junctions.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗