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PubMed2006

Genetic algorithms as a tool for helix design--computational and experimental studies on prion protein helix 1.

Evolutionary computing is a general optimization mechanism successfully implemented for a variety of numeric problems in a variety of fields, including structural biology. We here present an evolutionary approach to optimize helix stability in peptides and proteins employing the AGADIR energy function for helix stability as scoring function. With the ability to apply masks determining positions, which are to remain constant or fixed to a certain class of amino acids, our algorithm is capable of developing stable helical scaffolds containing a wide variety of structural and functional amino acid patterns. The algorithm showed good convergence behaviour in all tested cases and can be parameterized in a wide variety of ways. We have applied our algorithm for the optimization of the stability of prion protein helix 1, a structural element of the prion protein which is thought to play a crucial role in the conformational transition from the cellular to the pathogenic form of the prion protein, and which therefore poses an interesting target for pharmacological as well as genetic engineering approaches to counter the as of yet uncurable prion diseases. NMR spectroscopic investigations of selected stabilizing and destabilizing mutations found by our algorithm could demonstrate its ability to create stabilized variants of secondary structure elements.

Algorithms↗
PubMed1991

[Principles of ontogenetic (phenotype and genotype) variability of the maxillo-dental system].

By means of the computer a multiple regrouping of 1090 caucasians and 1035 Mongoloids at the age of 17-21 years and 98 (corpses) caucasian ++ men at the age of 17-38 years has been performed with a subsequent inter- and ++intra-grouping analysis of 27 variants of the structure of the maxillodental system separately for the lower and upper jaws. A certain regularity between enlargement of the teeth size, increasing angle of the lower jaw and decreasing size of the longitudinal and expressive dimensions of the jaws (in accordance with decreasing size of the spongy substance and its cells) has been revealed. It is accompanied with increasing caries and vice versa within all the groups studied. There are certain borders for individual variants in every group (race, sex, wide-, middle- and ++steno-osseous). The morphotypes of the maxillo-dental system revealed are constitutional. They are marker for ontogenic rates and help to explain peculiarities++ of its individual specific reactions to caries liability.

Adolescent↗
PubMed2004

Trapping the on-pathway folding intermediate of Im7 at equilibrium.

The four-helical protein Im7 folds via a rapidly formed on-pathway intermediate (k(UI)=3000 s(-1) at pH 7.0, 10 degrees C) that contains three (helices I, II and IV) of the four native alpha-helices. The relatively slow (k(IN)=300 s(-1)) conversion of this intermediate into the native structure is driven by the folding and docking of the six residue helix III onto the developing hydrophobic core. Here, we describe the structural properties of four Im7* variants designed to trap the protein in the intermediate state by disrupting the stabilising interactions formed between helix III and the rest of the protein structure. In two of these variants (I54A and L53AI54A), hydrophobic residues within helix III have been mutated to alanine, whilst in the other two mutants the sequence encompassing the native helix III was replaced by a glycine linker, three (H3G3) or six (H3G6) residues in length. All four variants were shown to be monomeric, as judged by analytical ultracentrifugation, and highly helical as measured by far-UV CD. In addition, all the variants denature co-operatively and have a stability (DeltaG(UF)) and buried hydrophobic surface area (M(UF)) similar to those of the on-pathway kinetic intermediate. Structural characterisation of these variants using 1-anilino-8-napthalene sulphonic acid (ANS) binding, near-UV CD and 1D (1)H NMR demonstrate further that the trapped intermediate ensemble is highly structured with little exposed hydrophobic surface area. Interestingly, however, the structural properties of the variants I54A and L53AI54A differ in detail from those of H3G3 and H3G6. In particular, the single tryptophan residue, located near the end of helix IV, and distant from helix III, is in a distinct environment in the two sets of mutants as judged by fluorescence, near-UV CD and the sensitivity of tryptophan fluorescence to iodide quenching. Overall, the results confirm previous kinetic analysis that demonstrated the hierarchical folding of Im7 via an on-pathway intermediate, and show that this species is a highly helical ensemble with a well-formed hydrophobic core. By contrast with the native state, however, the intermediate ensemble is flexible enough to change in response to mutation, its structural properties being tailored by residues in the sequence encompassing the native helix III.

Bacterial Proteins↗
PubMed2004

Nonclassical bonding in the novel structure of Ba2Bi3 and unexpected site preference in the coloring variant Ba2BiSb2.

The new phase Ba(2)Bi(3) crystallizes in the W(2)CoB(2) structure type. Its structure contains rigorously planar anionic layers of (4.6.4.6)(4.6(2))(2) nets with three- and four-bonded Bi, that are separated by Ba atoms. An unexpected site preference is observed in the coloring variant Ba(2)BiSb(2) with Sb occupying only the three-bonded sites. The nonclassical bonding in the anionic network can be rationalized from a reformulation of the Zintl concept as (Ba(2+))(2)[Bi(3)](3)(-)(e(-)). Bonding distances suggest that the extra electron fills Bi-Bi antibonding states. The densities of states obtained from TB-LMTO-ASA calculations show metallic character for both compounds.

Journal Article↗
PubMed1978

A new hemoglobin variant. HB Yatsushiro alpha 2 A beta 2 60 Val replaced by Leu.

This study was performed to establish the structural abnormality of a new hemoglobin variant discover-d in a Japanese patient with angina pectoris. The hybridization of the separated hemoglobin with canine hemoglobin revealed a beta-chain anomaly. Peptide betaTp-6 was found to be abnormally located on the peptide map of tryptic digests of the S-carboxymethylated beta-chain from the variant hemoglobin. A structural study on the abnormal betaTp-6 revealed that the variant hemoglobin differs from hemoglobin A by substitution of leucine for valine at residue 60 of the beta-chain. This new variant hemoglobin is designated as hemoglobin Yatsushiro after the name of the city where the propositus lived. The patient is hematologically healthy and his clinical history has nothing to do with this abnormal hemoglobin.

Genetic Code↗
PubMedDate not supplied

[Structure of flower in Arabidopsis thaliana: spatial pattern formation].

Morphological analysis of flowers was carried out in Arabidopsis thaliana wild type plants and agamous and apetala2 mutants. No direct substitution of organs takes place in the mutants, since the number and position of organs in them do not correspond to the structure of wild type flower. In order to explain these data, a notion of spatial pattern formation in the meristem was introduced, which preceded the processes of appearance of organ primordia and formation of organs. Zones of acropetal and basipetal spatial pattern formation in the flower of wild type plants were postulated. It was shown that the acropetal spatial pattern formation alone took place in agamous mutants and basipetal spatial pattern formation alone, in apetala2 mutants. Different variants of flower structure are interpreted as a result of changes in the volume of meristem (space) and order of spatial pattern formation (time).

AGAMOUS Protein, Arabidopsis↗
PubMed1998

Crystal structure of the arcelin-1 dimer from Phaseolus vulgaris at 1.9-A resolution.

Arcelin-1 is a glycoprotein from kidney beans (Phaseolus vulgaris) which displays insecticidal properties and protects the seeds from predation by larvae of various bruchids. This lectin-like protein is devoid of monosaccharide binding properties and belongs to the phytohemagglutinin protein family. The x-ray structure determination at 1.9-A resolution of native arcelin-1 dimers, which correspond to the functional state of the protein in solution, was solved using multiple isomorphous replacement and refined to a crystallographic R factor of 0.208. The three glycosylation sites on each monomer are all covalently modified. One of these oligosaccharide chains provides interactions with protein atoms at the dimer interface, and another one may act by preventing the formation of higher oligomeric species in the arcelin variants. The dimeric structure and the severe alteration of the monosaccharide binding site in arcelin-1 correlate with the hemagglutinating properties of the protein, which are unaffected by simple sugars and sugar derivatives. Sequence analysis and structure comparisons of arcelin-1 with the other insecticidal proteins from kidney beans, arcelin-5, and alpha-amylase inhibitor and with legume lectins, yield insights into the molecular basis of the different biological functions of these proteins.

Amino Acid Sequence↗
PubMed1990

Isolation and characterization of a second molybdopterin dinucleotide: molybdopterin cytosine dinucleotide.

The pterin cofactor (bactopterin) in the molybdoenzyme CO dehydrogenase isolated from Pseudomonas carboxydoflava has previously been shown to differ from molybdopterin in molecular mass, phosphate content, stability, and other properties, implying a novel structure. The structure of the CO dehydrogenase pterin has been investigated in the present studies by alkylation and isolation of the carboxamidomethyl derivative. The alkylated pterin was identified as [di-(carboxamidomethyl)]molybdopterin cytosine dinucleotide on the basis of its absorption properties and by degradation with nucleotide pyrophosphatase yielding carboxamidomethylmolybdopterin and CMP. Further treatment of these products with alkaline phosphatase produced species with absorption and chromatographic properties identical to those of the corresponding dephospho compounds. Molybdopterin cytosine dinucleotide is the second molybdopterin variant to be structurally characterized. The fact that molybdopterin cytosine dinucleotide and molybdopterin guanine dinucleotide contain molybdopterin in their structure shows that the pterin moiety, with its unique dithiolene-containing sidechain, is a structural element which is common to the organic portion of the molybdenum cofactors of many molybdoenzymes.

Aldehyde Oxidoreductases↗
PubMed1991

Beta-lactamase: lessons in the art of survival.

1. A beta-lactamase molecule is a marvelous device enabling its marker to thrive in a hostile and potentially lethal environment. What is more, the protective effect is extended to otherwise vulnerable organisms, securing their survival in the sheltered neighborhood. Curiously, such environmental implications had no discernible impact on the strategy of antibacterial chemotherapy. Moreover, traditional diagnostic routines are largely responsible for the sheltered survival of susceptible pathogens. 2. For half a century, since their existence was discovered by Abraham and Chain, beta-lactamases have never ceased to amaze us with an ever-widening spectrum of structural and functional variants, appearing in increasingly rapid succession in an ever broader range of bacteria. Whereas the phenomenon itself was the predicted outcome of unguarded expansion of beta-lactam therapy, its scope is a testimony to the unique advantage of an otherwise irrelevant, and thus freely modifiable and transmissible, enzyme as a key to survival. 3. Perhaps the least expected lesson is to be had from the adaptive behaviour of the beta-lactamase molecule itself. Faced with virtually countless structural variations on the beta-lactam theme, nearly all created so as to frustrate its function, the beta-lactamase molecule proves to be so versatile in overcoming so many of its potential inhibitors that it makes us reflect on the evolutionary significance of coping and survival at the molecular level.

Adaptation, Physiological↗
PubMed2005

Understanding GFP chromophore biosynthesis: controlling backbone cyclization and modifying post-translational chemistry.

The Aequorea victoria green fluorescent protein (GFP) undergoes a remarkable post-translational modification to create a chromophore out of its component amino acids S65, Y66, and G67. Here, we describe mutational experiments in GFP designed to convert this chromophore into a 4-methylidene-imidazole-5-one (MIO) moiety similar to the post-translational active-site electrophile of histidine ammonia lyase (HAL). Crystallographic structures of GFP variant S65A Y66S (GFPhal) and of four additional related site-directed mutants reveal an aromatic MIO moiety and mechanistic details of GFP chromophore formation and MIO biosynthesis. Specifically, the GFP scaffold promotes backbone cyclization by (1) favoring nucleophilic attack by close proximity alignment of the G67 amide lone pair with the pi orbital of the residue 65 carbonyl and (2) removing enthalpic barriers by eliminating inhibitory main-chain hydrogen bonds in the precursor state. GFP R96 appears to induce structural rearrangements important in aligning the molecular orbitals for ring cyclization, favor G67 nitrogen deprotonation through electrostatic interactions with the Y66 carbonyl, and stabilize the reduced enolate intermediate. Our structures and analysis also highlight negative design features of the wild-type GFP architecture, which favor chromophore formation by destabilizing alternative conformations of the chromophore tripeptide. By providing a molecular basis for understanding and controlling the driving force and protein chemistry of chromophore creation, this research has implications for expansion of the genetic code through engineering of modified amino acids.

Alanine↗
PubMed1994

Site-specific O-glycosylation of cell adhesive lysozyme in yeast.

The cell adhesive protein RGD8 has been constructed using a yeast expression system by inserting eight amino acid residues (TGRGDSPA) between Val74 and Asn75 of human lysozyme [Yamada et al. (1993) J. Biol. Chem. 268, 10588-10592]. Purified RGD8 from yeast culture supernatant was found to contain glycosylated variants, in addition to the unglycosylated form. Peptide mapping analyses suggested that the glycosylation occurred at the inserted Thr residue in the RGD8 molecule. Electrospray ionization mass spectrometric analysis demonstrated the presence of four or five hexose residues in the glycosylated variants. Only mannose was detected in the sugar analysis of the oligosaccharide mixture obtained by mild alkaline treatment of the variants, and the structures of these carbohydrate chains were identified as Man alpha 1-3Man alpha 1-2Man alpha 1-2Man alpha and Man alpha 1-3Man alpha 1-3Man alpha 1-2Man alpha 1-2Man alpha by 1H-NMR spectroscopy. No other glycosylation was found, although the RGD8 molecule possesses a total of 13 Thr and Ser residues. In addition, no O-glycosylation was observed when the RGD8 protein was expressed in mouse L-cells. Thus, this O-glycosylation looks specific for yeast and the site of the Thr residue. The O-glycosylated variants of RGD8 exhibited a high level of adhesion activity to baby hamster kidney cells, which was almost comparable to that of the unglycosylated form.

Amino Acid Sequence↗
PubMed1979

Restriction Maps of Five Autographa californica MNPV Variants, Trichoplusia ni MNPV, and Galleria mellonella MNPV DNAs with Endonucleases SmaI, KpnI, BamHI, SacI, XhoI, and EcoRI.

The restriction sites of Autographa californica nuclear polyhedrosis virus (AcMNPV) E2 DNA were mapped for the endonucleases SmaI, KpnI, BamHI, SacI, XhoI, and EcoRI. The restriction maps of four other AcMNPV variants, Trichoplusia ni (TnMNPV), and Galleria mellonella (GmMNPV) genomes were determined and compared to the endonuclease cleavage maps of AcMNPV E2 DNA. The viral structural polypeptides of AcMNPV variants S3, E2, S1, M3, and R9 were the same when analyzed by polyacrylamide gel electrophoresis. The major structural polypeptides of GmMNPV and TnMNPV had the same pattern in polyacrylamide gels as did AcMNPV structural polypeptides. GmMNPV and TnMNPV had several minor structural protein differences as compared with AcMNPV. AcMNPV variants, TnMNPV, and GmMNPV were distinct but with very similar genomes and protein structures.

Journal Article↗
PubMed2004

Haplotype block and superblock structures of the alpha1-adrenergic receptor genes reveal echoes from the chromosomal past.

A significant proportion of the human genome is contained within haplotype blocks across which pairwise linkage disequilibrium (LD) is very high. However, LD is also often high between markers at more remote distances, and within different haplotype blocks. Here, we evaluate the origins of haplotype block structure in the three genes for alpha1 adrenergic receptors (alpha1-AR) in the human genome ( ADRA1A, ADRA1B and ADRA1D) by genotyping dense single-nucleotide polymorphism (SNP) marker maps, and show that LD signals between distant markers are due to the presence of extended haplotype superblocks in individuals with ancient chromosomes which have escaped historic recombination. ARs mediate the physiological effects of epinephrine and norepinephrine, and are targets of many therapeutic drugs. This work has identified haplotype backgrounds of alpha1-AR missense variants, haplotype block structures in US Caucasians and African Americans, and haplotype tag SNPs for each block, and we present strong evidence for ancient haplotype block superstructure at these genes which has been partially disrupted by recombination, and evidence for reinstatement of linkage disequilibrium by subsequent recombination events. ADRA1A is comprised of four haplotype blocks in US Caucasians, while in African Americans Block 1 is split. ADRA1B has four blocks in US Caucasians, but in African Americans only the first two blocks are present. ADRA1D has two blocks in US Caucasians, and the first block is replaced by two smaller blocks in African Americans. For both ADRA1A and ADRA1B, haplotype superstructures may represent a novel, higher-level hierarchy in the human genome, which may reduce redundancy of testing by further aggregation of genotype data.

Black or African American↗
PubMed1992

Apes and apomorphies: the anterior nasal spine as a projection of cladistic conceptions.

Projections, tubercles, or spines of bone at the anterior margin of the piriform aperture occur in widely varying forms among catarrhine primates. This paper describes, illustrates, and tabulates the frequencies of such structures by age and sex in a large collection of Pan troglodytes verus skulls. In the overall sample of 263 skulls where the region could be observed, these protuberances of bone occur bilaterally in 10.7% of specimens and unilaterally in an additional 3.4%. They increase in frequency with age to a high of 16.9% in adult and older animals. Among adult specimens, these projections of bone in the anterior nasal region are present more commonly in females than in males. In a comparative context, variants on this structure in nonhuman primates, some of them documented previously, should help to counter the cladistic conception that the anterior nasal spine is an apomorphic or evolutionary novel morphological structure in hominids.

Age Factors↗
PubMed1980

A single amino acid substitution (Asp leads to Asn) in a phosphoglycerate kinase variant (PGK München) associated with enzyme deficiency.

The structural abnormality of the phosphoglycerate kinase variant, PGK München, associated with red cell enzyme deficiency and heat instability, was elucidated by a microscale peptide-mapping method. A single amino acid substitution, from aspartic acid in the normal enzyme to asparagine in the variant enzyme, was found. From the known amino acid sequence of normal human phosphoglycerate kinase, the substitution is in the aspartic acid residue located at 268th position from the NH2-terminal of the protein.

Amino Acid Sequence↗
PubMed1996

Mobile unnatural amino acid side chains in the core of staphylococcal nuclease.

The structures of several variants of staphylococcal nuclease with long flexible unnatural amino acid side chains in the hydrophobic core have been determined by X-ray crystallography. The unnatural amino acids are disulfide moieties between the lone cysteine residue in V23C nuclease and methane, ethane, 1-n-propane, 1-n-butane, 1-n-pentane, and 2-hydroxyethyl thiols. We have examined changes in the core packing of these mutants. Side chains as large as the 1-n-propyl cysteine disulfide can be incorporated without perturbation of the structure. This is due, in part, to cavities present in the wild-type protein. The longest side chains are not well defined, even though they remain buried within the protein interior. These results suggest that the enthalpy-entropy balance that governs the rigidity of protein interiors favors tight packing only weakly. Additionally, the tight packing observed normally in protein interiors may reflect, in part, the limited numbers of rotamers available to the natural amino acids.

Amino Acids↗
PubMed2005

Four molecules of the 33 kDa haemagglutinin component of the Clostridium botulinum serotype C and D toxin complexes are required to aggregate erythrocytes.

Normally, large-sized botulinum toxin complexes (L-TC) of serotype C and D are composed of a single neurotoxin, a single non-toxic non-haemagglutinin, two HA-70 molecules, four HA-33 molecules and four HA-17 molecules that assemble to form a 650 kDa L-TC. The 540 and 610 kDa TC species (designated here as L-TC2 and L-TC3, respectively) were purified in addition to the 650 kDa L-TC from the culture supernatants of serotype D strains (D-4947 and D-CB16) and serotype C strains (C-6814 and C-Yoichi). The 650 kDa L-TC from D-4947, D-CB16 and C-6814 showed haemagglutination and erythrocyte-binding activity, but their L-TC2 and L-TC3 species had only binding activity. In contrast, every TC species from C-Yoichi having the C-terminally truncated variant of HA-33 exhibited neither haemagglutination activity nor erythrocyte-binding activity. Four strain-specific HA-33/HA-17 complexes were isolated from the 650 kDa L-TC of each strain. The 650 kDa HA-hybrid L-TCs were reconstituted by various combinations of isolated HA-33/HA-17 complexes and haemagglutination-negative L-TC2 or L-TC3 from each strain. HA-hybrid 650 kDa L-TC, including at least one HA-33/HA-17 complex derived from C-Yoichi, lost haemagglutination activity, leading to the conclusion that the binding of four HA-33 molecules is required for haemagglutination activity of botulinum L-TC. The results of the modelling approach indicated that the structure of a variant C-Yoichi HA-33 molecule reveals clear deformation of the beta-trefoil domain responsible for the carbohydrate recognition site.

Botulinum Toxins↗
PubMed1995

Bulged-out nucleotides protect an antisense RNA from RNase III cleavage.

Bulged-out nucleotides or internal loops are present in the stem-loop structures of several antisense RNAs. We have used the antisense/target RNA system (CopA/CopT) that controls the copy number of plasmid R1 to examine the possible biological function of bulged-out nucleotides. Two regions within the major stem-loop of the antisense RNA, CopA, carry bulged-out nucleotides. Base pairing in either one or both of these regions of the stem was restored by site-specific mutagenesis and in one case a new internal loop was introduced. The set of mutant and wild-type CopA variants was characterized structurally in vitro. The results reported here indicate a possible function of the bulges: their presence protects CopA RNA from being a substrate for the double-strand-specific enzyme RNase III. In vitro cleavage rates were drastically increased when either the lower or both bulges were absent. This is paralleled by a similar, but not identical, effect of the bulges on metabolic stability of the CopA RNAs in vivo. The degradation pathways of wild-type and mutant CopA in various strain backgrounds are discussed. In the accompanying paper, we address the significance of bulges in CopA for binding to the target RNA in vitro and for its inhibitory efficiency in vivo.

Bacterial Proteins↗