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PubMed2005

Structural analysis of leucine-rich-repeat variants in proteins associated with human diseases.

A number of human diseases have been shown to be associated with mutation in the genes encoding leucine-rich-repeat (LRR)-containing proteins. They include 16 different LRR proteins. Mutations of these proteins are associated with 19 human diseases. The mutations occur frequently within the LRR domains as well as their neighboring domains, including cysteine clusters. Here, based on the sequence analysis of the LRR domains and the known structure of LRR proteins, we describe some features of different sequence variants and discuss their adverse effects. The mutations in the cysteine clusters, which preclude the formation of sulfide bridges or lead to a wrong paring of cysteines in extracellular proteins or extracellular domains, occur with high frequency. In contrast, missense mutations at some specific positions in LRRs are very rare or are not observed at all.

Genetic Diseases, Inborn↗
PubMed1991

Structure and genetic variability of envelope glycoproteins of two antigenic variants of caprine arthritis-encephalitis lentivirus.

To define the structure of the caprine arthritis-encephalitis virus (CAEV) env gene and characterize genetic changes which occur during antigenic variation, we sequenced the env genes of CAEV-63 and CAEV-Co, two antigenic variants of CAEV defined by serum neutralization. The deduced primary translation product of the CAEV env gene consists of a 60- to 80-amino-acid signal peptide followed by an amino-terminal surface protein (SU) and a carboxy-terminal transmembrane protein (TM) separated by an Arg-Lys-Lys-Arg cleavage site. The signal peptide cleavage site was verified by amino-terminal amino acid sequencing of native CAEV-63 SU. In addition, immunoprecipitation of [35S]methionine-labeled CAEV-63 proteins by sera from goats immunized with recombinant vaccinia virus expressing the CAEV-63 env gene confirmed that antibodies induced by env-encoded recombinant proteins react specifically with native virion SU and TM. The env genes of CAEV-63 and CAEV-Co encode 28 conserved cysteines and 25 conserved potential N-linked glycosylation sites. Nucleotide sequence variability results in 62 amino acid changes and one deletion within the SU and 34 amino acid changes within the TM.

Amino Acid Sequence↗
PubMed1998

The short and long forms of type XVIII collagen show clear tissue specificities in their expression and location in basement membrane zones in humans.

Two N-terminal ends of human type XVIII collagen chains have recently been identified. The two chains have different signal peptides and variant N-terminal noncollagenous NC1 domains of 493 (NC1-493) and 303 (NC1-303) amino acid residues, respectively, but share 301 residues of their NC1 domains as well as the collagenous and C-terminal noncollagenous portions of the molecule. Antibodies were produced against the NC1 region common to both human alpha1(XVIII) chain variants and against NC1 sequences specific to the long variant and were used in combination with in situ hybridization to localize this collagen in a number of human tissues. They were also used for Western blotting, which resulted in detection of overlapping high-molecular weight bands above the 200-kd standard in a kidney extract. Heparin lyase II and heparin lyase III digestions of kidney and placenta extracts indicated that at least in these tissues, type XVIII collagen contains heparin sulfate glycosaminoglycan side chains. Type XVIII collagen was found to be a ubiquitous basement membrane component, occurring prominently at vascular and epithelial basement membranes throughout the body. Comparison of the expression of the NC1-493 and NC1-303 variants revealed marked differences. The short variant was found in most conventional basement membranes, including blood vessels and the various epithelial structures, and around muscular structures. The long variant was expressed very strongly in liver, where it was virtually the only variant in the liver sinusoids, and it occurred only in minor amounts elsewhere. Thus, the 192 N-terminal residues specific to the long variant apparently confer some functional property needed above all in the liver sinusoids, but also at certain other locations.

Antibodies↗
PubMed2004

Using networks to identify fine structural differences between functionally distinct protein states.

The vast increase in available data from the "-omics" revolution has enabled the fields of structural proteomics and structure prediction to make great progress in assigning realistic three-dimensional structures to each protein molecule. The challenge now lies in determining the fine structural details that endow unique functions to sequences that assume a common fold. Similar problems are encountered in understanding how distinct conformations contribute to different phases of a single protein's dynamic function. However, efforts are hampered by the complexity of these large, three-dimensional molecules. To overcome this limitation, structural data have been recast as two-dimensional networks. This analysis greatly reduces visual complexity but retains information about individual residues. Such diagrams are very useful for comparing multiple structures, including (1) homologous proteins, (2) time points throughout a dynamics simulation, and (3) functionally different conformations of a given protein. Enhanced structural examination results in new functional hypotheses to test experimentally. Here, network representations were key to discerning a difference between unliganded and inducer-bound lactose repressor protein (LacI), which were previously presumed to be identical structures. Further, the interface of unliganded LacI was surprisingly similar to that of the K84L variant and various structures generated by molecular dynamics simulations. Apo-LacI appears to be poised to adopt the conformation of either the DNA- or inducer-bound structures, and the K84L mutation appears to freeze the structure partway through the conformational transition. Additional examination of the effector binding pocket results in specific hypotheses about how inducer, anti-inducer, and neutral sugars exert their effects on repressor function.

Bacterial Proteins↗
PubMed2001

Preparation and crystal structure of the ternary uranium rare Earth antimonides (U(2/3)R(1/3))Sb(2) and (U(1/2)R(1/2))(3)Sb(7) with mixed U/R occupancy of the metal sites and a variety of antimony polyanions.

The ternary antimonides (U(2/3)R(1/3))Sb(2) (R = Y, Ce-Nd, Sm, Gd-Tm) and (U(1/2)R(1/2))(3)Sb(7) (R = Y, Gd-Ho) have been prepared by reaction of the uranium antimonide USb(2) with the corresponding rare earth antimonides RSb(2) and an excess of elemental antimony at high temperatures. The crystal structure of the isotypic series (U(2/3)R(1/3))Sb(2) has been determined from single-crystal X-ray data of (U(0.675(9))Gd(0.325(9)))Sb(2). It is isotypic with PbCl(2): Pnma, Z = 4, a = 754.6(1), b = 419.6(1), c = 1025.7(3) pm. The compounds of the other series crystallize with a new structure type, which has been determined for (U(0.49(1))Ho(0.51(1)))(3)Sb(7): Immm, Z = 4, a = 410.1(1), b = 1447.7(3), c = 1821.2(5) pm. In both structures, the metal positions have mixed occupancy and high coordination numbers. Both structures contain numerous weak Sb-Sb bonds, thus forming a band of antimony atoms in the structure of (U(2/3)Gd(1/3))Sb(2) and a chain and a three-dimensionally infinite network of antimony atoms in the structure of (U(1/2)Ho(1/2))(3)Sb(7). Analyses of the Sb-Sb bonding within the antimony polyanions on the basis of bond-length bond-strength considerations indicate that the uranium atoms have mixed or intermediate +3/+4 valence in these compounds. The structure of (U(1/2)Ho(1/2))(3)Sb(7) may be considered as a defect variant of the structure of Ce(6)MnSb(15).

Journal Article↗
PubMed2002

Crystal structure of Lyme disease variable surface antigen VlsE of Borrelia burgdorferi.

VlsE is an outer surface lipoprotein of Borrelia burgdorferi that undergoes antigenic variation through an elaborate gene conversion mechanism and is thought to play a major role in the immune response to the Lyme disease borellia. The crystal structure of recombinant variant protein VlsE1 at 2.3-A resolution reveals that the six variable regions form loop structures that constitute most of the membrane distal surface of VlsE, covering the predominantly alpha-helical, invariant regions of the protein. The surface localization of the variable amino acid segments appears to protect the conserved regions from interaction with antibodies and hence may contribute to immune evasion.

Amino Acid Sequence↗
PubMedDate not supplied

Thymus and thymoma: what's new?

The thymus is the prototype of lymphoid and epithelial organ that consists of lymphoid and epithelial cells. In spite of remarkable progresses made in the field of the immunohistochemical characterisation of the thymus parenchyma, the diagnosis of thymoma largely depends on the interpretation of conventional morphologic aspects. Histogenesis of this organ is a multi-step process, and many stages reproduce lesions and changes found in the adult thymus. The normal structure and its variants are extremely helpful to differentiate normal from pathologic aspects. Particular aspects of the thymus structures were shown in myasthenia gravis, despite the behaviour of thymoma in these patients is not clearly understood. Authors performed a detailed description of the conventional pathology of the thymoma, based on the new classifications, recently adopted. The immunohistochemical profile could be helpful in the diagnosis of many cases, and also seems to be useful in prediction of invasion that is the most important criterion in prognosis.

Humans↗
PubMed2000

A comparative analysis of 23 structures of the amyloidogenic protein transthyretin.

Self-assembly of the human plasma protein transthyretin (TTR) into unbranched insoluble amyloid fibrils occurs as a result of point mutations that destabilize the molecule, leading to conformational changes. The tertiary structure of native soluble TTR and many of its disease-causing mutants have been determined. Several independent studies by X-ray crystallography have suggested structural differences between TTR variants which are claimed to be of significance for amyloid formation. As these changes are minor and not consistent between the studies, we have compared all TTR structures available at the protein data bank including three wild-types, three non-amyloidogenic mutants, seven amyloidogenic mutants and nine complexes. The reference for this study is a new 1.5 A resolution structure of human wild-type TTR refined to an R-factor/R-free of 18.6 %/21.6 %. The present findings are discussed in the light of the previous structural studies of TTR variants, and show the reported structural differences to be non-significant.

Crystallography, X-Ray↗
PubMed1999

Structural and spectral response of green fluorescent protein variants to changes in pH.

The green fluorescent protein (GFP) from the jellyfish Aequorea victoria has become a useful tool in molecular and cell biology. Recently, it has been found that the fluorescence spectra of most mutants of GFP respond rapidly and reversibly to pH variations, making them useful as probes of intracellular pH. To explore the structural basis for the titration behavior of the popular GFP S65T variant, we determined high-resolution crystal structures at pH 8.0 and 4.6. The structures revealed changes in the hydrogen bond pattern with the chromophore, suggesting that the pH sensitivity derives from protonation of the chromophore phenolate. Mutations were designed in yellow fluorescent protein (S65G/V68L/S72A/T203Y) to change the solvent accessibility (H148G) and to modify polar groups (H148Q, E222Q) near the chromophore. pH titrations of these variants indicate that the chromophore pKa can be modulated over a broad range from 6 to 8, allowing for pH determination from pH 5 to pH 9. Finally, mutagenesis was used to raise the pKa from 6.0 (S65T) to 7.8 (S65T/H148D). Unlike other variants, S65T/H148D exhibits two pH-dependent excitation peaks for green fluorescence with a clean isosbestic point. This raises the interesting possibility of using fluorescence at this isosbestic point as an internal reference. Practical real time in vivo applications in cell and developmental biology are proposed.

Amino Acid Substitution↗
PubMed1999

Solution structure and dynamics of a designed hydrophobic core variant of ubiquitin.

BACKGROUND: The recent merger of computation and protein design has resulted in a burst of success in the generation of novel proteins with native-like properties. A critical component of this coupling between theory and experiment is a detailed analysis of the structures and stabilities of designed proteins to assess and improve the accuracy of design algorithms. RESULTS: Here we report the solution structure of a hydrophobic core variant of ubiquitin, referred to as 1D7, which was designed with the core-repacking algorithm ROC. As a measure of conformational specificity, we also present amide exchange protection factors and backbone and sidechain dynamics. The results indicate that 1D7 is similar to wild-type (WT) ubiquitin in backbone structure and degree of conformational specificity. We also observe a good correlation between experimentally determined sidechain structures and those predicted by ROC. However, evaluation of the core sidechain conformations indicates that, in general, 1D7 has more sidechains in less statistically favorable conformations than WT. CONCLUSIONS: Our results provide an explanation for the lower stability of 1D7 compared to WT, and suggest modifications to design algorithms that may improve the accuracy with which structure and stability are predicted. The results also demonstrate that core packing can affect conformational flexibility in subtle ways that are likely to be important for the design of function and protein-ligand interactions.

Algorithms↗
PubMed1993

The carbohydrate structures of Trypanosoma brucei brucei MITat 1.6 variant surface glycoprotein. A re-investigation of the C-terminal glycan.

We have studied the oligosaccharide chains of the variant surface glycoprotein (VSG) of Trypanosoma brucei brucei MITat 1.6. Glycopeptides were generated by Pronase digestion, purified by gel permeation and ion-exchange chromatography, and structurally characterized by 1H and 31P NMR spectroscopy in combination with chemical composition analyses. The two glycopeptide fractions obtained each proved to be homogeneous in their peptide and heterogeneous in their carbohydrate structures. The fraction representing the "internal" N-glycosylation site of the VSG was found to contain high-mannose type oligosaccharides with structures Man7-9GlcNAc2 linked to Asn-Ala-Thr. The other glycopeptide fraction contained the membrane-anchoring C-terminal glycan of the VSG attached to Asp. Its oligosaccharide structures are of the glycosylphosphatidylinositol (GPI) type: [structure: see text] This structure includes revisions of multiple structural features published for the GPI anchor of T. b. brucei MITat 1.6 VSG by Schmitz et al. (1987) Biochem. Biophys. Res. Commun. 146: 1055-1063.

Animals↗
PubMed2001

Characterization of the mouse integrin subunit alpha10 gene and comparison with its human homologue. Genomic structure, chromosomal localization and identification of splice variants.

Alpha10beta1 is a collagen-binding integrin expressed by chondrocytes [Camper et al. (1998) J. Biol. Chem. 273: 20383-20389]. In the present study, the mouse alpha10 gene was isolated from a sCos1 SVJ library and the genomic structure and chromosomal localization was determined. The alpha10 gene consists of 30 translated exons spanning a region of approximately 18 kb genomic DNA. The sequences of all exon/intron borders follow the consensus "gt-ag" rule. A transcription start site, determined by primer extension analysis, was located 38 nucleotides upstream of the initiation ATG site. The 5' flanking region of the transcription start site lacked a TATA-box. The first exon contained, in addition to 38 untranslated nucleotides, the ATG translation start site and the major part of the signal peptide. The alpha10 gene was mapped to mouse chromosome 3 by fluorescence in situ hybridization and is the only integrin subunit localized to this chromosome. When we investigated the expression of alpha10 by PCR we found that both mouse and human articular chondrocytes express extracellular splice variants of the alpha10 subunit. In mouse, exon 26 was extended into the intron by 62 nt, generating a truncated alpha10-chain. In human, exon 25 consisted of 114 nt which were alternately spliced in or out.

Alternative Splicing↗
PubMedDate not supplied

[2 variants of the radioimmunochemical method of determination of LH-releasing factor (LH-RF). Distribution of LH-RF in various hypothalamic structures].

The authors elaborated two variants of the radioimmunochemical method of determination of the LH-releasing factor (LH-RF). Diluted antisera (AS) obtained by the immunization of rabbits with the LH-RF-ovalbumin were used in the first method; AS polymerized with isobutyl ester of chlorcarbonic acid were used in the second one. The minimal amount of the hormone determined in the I variant was 5 pg, and in the 11 one--20 to 30 pg. The method is highly specific, since the antisera gave no cross reaction with a wide set of protein-peptide hormones synthesized with the hypothalamus and the hypophysis. The presence in the samples of tissue components of the hypothalamus and of the cerebral cortex extractable with 2M CH3COOH failed to influence the precision of the test. In examining the LH-RF content in the brain structures there was revealed that in the sexually mature male rats the whole hypothalamus contained an average of 7.5 ng, the arcuate nuclei--1.5 ng and the medial eminence--2.5 ng of LH-RF; the supraoptic nuclei and the cerebral cortex contained no LH-RF determinable by the method described. Two weeks after the castration the mean content of the hormone in the whole hypothalamus decreased to 5.5 ng, in the medial eminence--to 0.6 ng, and showed no significant change in the arcuate nuclei.

Animals↗
PubMed1993

Relocating a negative charge in the binding pocket of trypsin.

The functional and structural consequences of altering the position of the negatively charged aspartate residue at the base of the specificity pocket of trypsin have been examined by site-directed mutagenesis, kinetic characterization and crystallographic analysis. Anionic rat trypsin D189G/G226D exhibits a high level of catalytic activity on activated amide substrates, but its relative preference for lysine versus arginine as the P1 site residue is shifted by 30 to 40-fold in favor of lysine. The crystal structure of this variant has been determined in complexes with BPTI (bovine pancreatic trypsin inhibitor), APPI (amyloid beta-protein precursor inhibitor domain) and benzamidine inhibitors, at resolutions of 2.1 A, 2.5 A and 2.2 A, respectively. Asp226 bridges the base of the specificity pocket with its negative charge partially buried by interactions made with Ser190 and Tyr228. An equal reduction in the affinity of the variant enzyme for Arg and Lys substrates is attributable to a decreased electrostatic interaction of each ligand with the relocated aspartate residue. Comparison of structural and functional parameters with those of wild-type trypsin suggests that direct hydrogen-bonding electrostatic contacts in the S1 site do not significantly improve the free energy of substrate binding relative to indirect water-mediated interactions. The conformation adopted by Asp226, as well as by other adjacent side-chain and backbone groups, depends upon the ligand bound in the primary specificity pocket. This structural flexibility may be of critical importance to the retention of catalytic activity by the variant enzyme.

Animals↗
PubMed1989

Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant.

A family has been described in which type III hyperlipoproteinemia is associated with apo E phenotype E3/3 (Havel, R. J., L. Kotite, J. P. Kane, P. Tun, and T. Bersot. 1983. J. Clin. Invest. 72:379-387). In the current study, the structure of apo E from the propositus of this family was determined using both protein and DNA analyses. The propositus is heterozygous for two different apo E alleles, one coding for normal apo E3 and one for a previously undescribed variant apo E3 in which arginine replaces cysteine at residue 112 and cysteine replaces arginine at residue 142. Apo E gene analysis of nine other family members spanning four generations indicated that only those five members having type III hyperlipoproteinemia possess the variant apo E3. Like the propositus, all five are heterozygous for this variant, suggesting that the disorder in this family is transmitted in a dominant fashion. The variant apo E3 was defective in its ability to bind to lipoprotein receptors, and this functional defect probably contributes to the expression of type III hyperlipoproteinemia in this family.

Adult↗
PubMed1989

[Phospholipid content of subcellular structures in skeletal muscles after halothane loading in Landrace swine in relation to mating variants and genotype].

Membraneous phospholipids of subcellular structures were determined from the musculature of German Landrace pigs of the GDR, following exposure to halothane. Mating variants A (H+ male X H+ female), B (H+ male X H- female), and C (H- male X H+ female) were used for positive responders (MHS), while variants B, C, and D (H- male X H- female) were used for negative responders (MHN). Four phospholipid fractions were recorded from the muscle samples for mitochondria and microsomes (according to SR section). Differences between the MHS and MHN groups for the above fractions and without consideration of mating variants and genotype were not observed, although unambiguous responses were exhibited by all animals, either positive or negative to halothan. Significant differences with regard to the above phospholipid fractions were recordable only for variant A (MHS group) as compared to D (MHN), in other words, for the homozygous genotypes, once the above results had been rearranged within MHS and MHN along with different mating variants and genotypes. However, no unambiguous results were obtainable for the heterozygous genotypes of mating variants B and C. Possible underlying reasons are discussed in some detail. The results obtained from mating variants A and D are likely to confirm earlier findings and seem to suggest that the sarcoplasmic reticulum is the primary site of origin of susceptibility to halothane or malignant hyperthermia.

Animals↗
PubMed2005

"Wide-open" 1.3 A structure of a multidrug-resistant HIV-1 protease as a drug target.

This report examines structural changes in a highly mutated, clinical multidrug-resistant HIV-1 protease, and the crystal structure has been solved to 1.3 A resolution in the absence of any inhibitor. This protease variant contains codon mutations at positions 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90 that confer resistance to protease inhibitors. Major differences between the wild-type and the variant include a structural change initiated by the M36V mutation and amplified by additional mutations in the flaps of the protease, resulting in a "wide-open" structure that represents an opening that is 8 A wider than the "open" structure of the wild-type protease. A second structural change is triggered by the L90M mutation that results in reshaping the 23-32 segment. A third key structural change of the protease is due to the mutations from longer to shorter amino acid side chains at positions 82 and 84.

Amino Acid Sequence↗
PubMed2026

Somatic mutations and genome mosaicism in aging and disease.

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging.

Humans↗