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Query: UNIPROT:P06889 (Mol)
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Single crystals of a complex of gramicidin A, a transmembrane channel-forming polypeptide, and dipalmitoyl phosphatidylcholine, a phospholipid, have been prepared and characterized by X-ray diffraction. They belong to space group P222(1), with unit cell dimensions a = 26.8 A, b = 27.5 A, c = 32.8 A. The asymmetric unit appears to be a complex of one gramicidin monomer and two phospholipid molecules. The unit cell dimensions, space group, and chemical composition are compatible with lipids packing in a bilayer-like motif, and an end-to-end association of gramicidin monomers to form a functional dimeric unit. The crystals diffract to 2 A and are suitable for structural studies by single-crystal X-ray analysis. This represents the first example of a well-ordered crystalline channel complexed with lipids, and solution of its structure may give insight into mechanisms of ion transport across membranes.
J Mol Biol 1991 Feb 20
PMID:Co-crystals of gramicidin A and phospholipid. A system for studying the structure of a transmembrane channel. 170 36

The existing classification of human Alu sequences is revised and expanded using a novel methodology and a larger set of sequence data. Our study confirms that there are two major Alu subfamilies, Alu-J and Alu-S. The Alu-S subfamily consists of at least five distinct subfamilies referred to as Alu-Sx, Alu-Sq, Alu-Sp, Alu-Sc, and Alu-Sb. The Alu-Sp and Alu-Sq subfamilies have been revealed by this study. Alu subfamilies differ from one another in a number of positions called diagnostic. In this paper the diagnostic positions are defined in quantitative terms and are used to evaluate statistical significance of the observed subfamilies. Each Alu subfamily most likely represents pseudogenes retroposed from evolving functional source Alu genes. Evidence presented in this paper indicates that Alu-Sp and Alu-Sc pseudogenes were retroposed from different source genes, during overlapping periods of time, and at different rates. Our analysis also indicates that the previously identified Alu-type transcript BC200 comes from an active Alu gene that might have existed even before the origin of dimeric Alu sequences. The source genes for Alu pseudogene families are reconstructed. It is assumed that diagnostic differences between reconstructed source genes reflect mutations that have occurred in true source Alu genes under natural selection. Some of these mutations are compensatory and are used to reconstruct a common secondary structure of Alu RNAs transcribed from the source genes. The biological function of Alu RNA is discussed in the context of its homology to the elongation-arresting domain of 7SL RNA.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Evol 1991 Feb
PMID:Reconstruction and analysis of human Alu genes. 170 81

In an attempt to define domains in insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) that are involved in IGF binding, we subjected the carboxyl end of the coding region of IGFBP-1 cDNA to mutagenesis. Mutant cDNAs were isolated, characterized by sequencing, and cloned in an expression vector under control of the simian virus-40 (SV40) early promoter. The constructs were transfected into COS-1 cells, and the mutant proteins, secreted into the culture medium, were analyzed for IGF binding by ligand blotting. The results obtained show that deletion of the C-terminal 20 amino acids or introduction of frame-shifts in this region resulted in loss of IGF binding and for some mutants in the formation of dimeric IGFBP-1 molecules. These dimers are probably formed when cysteine-226 (Cys-226) is missing, and its putative partner is able to form intermolecular disulfide bonds. Site-directed mutagenesis demonstrated that most of the introduced point mutations in the C-terminal region did not affect IGF binding. Only mutation of Cys-226 to tyrosine completely abolished IGF binding, as did the introduction of a negatively charged amino acid in the vicinity of this residue. Again, dimers were observed, supporting that Cys-226 is essential for the conformation of IGFBP-1. In addition, our data suggest that an IGF-binding domain may be located in the vicinity of the intramolecular disulfide bond formed by Cys-226 and its putative partner.
Mol Endocrinol 1991 Jul
PMID:Mutations in the C-terminal part of insulin-like growth factor (IGF)-binding protein-1 result in dimer formation and loss of IGF binding capacity. 171 84

Three different epitopes of the human IL-6 (IL-6) molecule were recognized by the mAb B-E4 (IgG2b), B-E8 (IgG1) and B-F6 (IgG1). The affinities of these three mAb for IL-6 differ little in several assays but if ranked by affinity they fall into the following order B-E8 greater than B-E4 greater than B-F6. B-E4 and B-E8 mAb, recognizing two different epitopes, are inhibiting mAb in the bioassay with the IL-6 depending cell line B9, however B-E8 has an inhibiting activity higher than B-E4. Both human natural IL-6 (HnIL-6) and human recombinant IL-6 (HrIL-6) were inhibited but not the murine natural IL-6 (MnIL-6). Surprisingly, not only the non-inhibiting mAb (B-F6) recognizes the HrIL-6 fixed to the receptor but also the inhibiting mAb B-E4 and B-E8. This together with the results obtained in a sandwich ELISA where the same mAb was used as both catcher and tracer to detect HrIL-6, it was concluded that dimeric HrIL-6 is able to fix the IL-6 receptor. Competition studies between monomeric HnIL-6 and dimeric HrIL-6 showed that the affinity of the dimeric HrIL-6 for the receptor was higher than that of HnIL-6.
Mol Immunol 1991 Nov
PMID:Human recombinant dimeric IL-6 binds to its receptor as detected by anti-IL-6 monoclonal antibodies. 172 May 1

The Responder (Rsp) locus of Drosophila melanogaster, the target locus of segregation distortion, is a satellite DNA array. This repeat array imparts some fitness advantage to the chromosomes bearing it. In this paper, we report the following three related molecular properties of this satellite repeat: (1) Sequence-directed curvature--On a polyacrylamide gel, Rsp-containing fragments migrate slower than would be predicted on the basis of their physical sizes. The extent of migration retardation correlates with the size and position of the Rsp sequence in a DNA fragment, suggesting that Rsp DNA is bent. The bending is shown to be affected by a DNA-binding drug (Hoechst 33258). (2) Nucleosome structure--Nucleosomes associated with Rsp repeats have an unusual spacing pattern. Instead of being spaced at approximately 190-bp intervals as is the bulk chromatin, they are separated at approximately 240-bp intervals, roughly the size of a dimeric Rsp repeat. The nucleosomal structure in the Rsp region is preferentially disrupted by Hoechst 33258, whereas the bulk chromatin appears to be insensitive to the drug. (3) Rsp-DNA binding proteins--Gel mobility-shift assays using nuclear extracts from pupae and end-labeled Rsp repeat demonstrate the presence of three distinct DNA-protein complexes. Competition assays suggest that these complexes are specific to the Rsp sequence, and two of these nucleoprotein complexes seem to be influenced by the presence of Hoechst 33258. The observed complexes are formed by nonhistone proteins of somatic origin and may be related to the normal functions of Rsp, rather than to the germ-line segregation distortion activities.
Mol Biol Evol 1991 Sep
PMID:Molecular analysis of the responder satellite DNA in Drosophila melanogaster: DNA bending, nucleosome structure, and Rsp-binding proteins. 172 53

In Moloney murine leukemia virus, the encapsidation Psi element was shown to be necessary and sufficient to promote packaging of viral RNA, and to be required for dimerization. The conformation of the Psi domain (nucleotides 215 to 565) was investigated in solution by chemical probing. The four bases were monitored at one of their Watson-Crick positions with dimethylsulfate at cytosine N3 and adenosine N1, and with a carbodiimide derivative at guanosine N1 and uridine N3. Position N7 of adenine residues was probed with diethylpyrocarbonate. The analyses were conducted on in vitro transcribed fragments corresponding either to the isolated Psi domain or to the 5'-terminal 725 nucleotides. The RNA fragments were analyzed in their monomeric and dimeric forms. A secondary structure model was derived from probing data, computer prediction and sequence analysis of related murine retroviruses. One major result is that Psi forms an independent and highly structured domain. Dimerization induces an extensive reduction of reactivity in region 278 to 309 that can be interpreted as the result of intermolecular interactions and/or intramolecular conformational rearrangements. A second region (around position 215) was shown to display discrete reactivity changes upon dimerization. These two regions represent likely elements of dimerization. More unexpectedly, reactivity changes (essentially enhancement of reactivity) were also detected in another part of Psi (around position 480) not believed to contain elements of dimerization. These reactivity changes could be interpreted as dimerization-induced allosteric transitions.
J Mol Biol 1992 Jan 05
PMID:Effect of dimerization on the conformation of the encapsidation Psi domain of Moloney murine leukemia virus RNA. 173 Oct 69

The three-dimensional structure of the highly thermostable 3-isopropylmalate dehydrogenase (IPMDH) from Thermus thermophilus has been determined by the multiple isomorphous replacement method and refined to 2.2 A resolution. The final R-factor is 0.185 for 20,307 reflections. The crystal asymmetric unit has one subunit consisting of 345 amino acid residues. The polypeptide chain of this subunit is folded into two domains (first and second domains) with parallel alpha/beta motifs. The domains are similar in their conformations and folding topologies, but differ from those of the NAD-binding domains of such well-known enzymes as the alcohol and lactate dehydrogenases. A beta-strand that is a part of the long arm-like polypeptide protruding from the second domain comes into contact with another subunit and contributes to the formation of an isologous dimer with a crystallographic 2-fold symmetry. Close subunit contacts are also present at two alpha-helices in the second domain. These helices strongly interact hydrophobically with the corresponding helices of the other subunit to form a hydrophobic core at the center of the dimer. Two large pockets that exist between the first domain of one subunit and the second domain of the other include the amino acid residues responsible for substrate binding. These results indicate that the dimeric form is essential for the IPMDH to express enzymatic activity and that the close subunit contact at the hydrophobic core is important for the thermal stability of the enzyme.
J Mol Biol 1991 Dec 05
PMID:Three-dimensional structure of a highly thermostable enzyme, 3-isopropylmalate dehydrogenase of Thermus thermophilus at 2.2 A resolution. 174 99

A disulfide-rich domain, first identified in wheat germ agglutinin, has now been identified in the amino acid and DNA sequences of a large number of other chitin-binding proteins. This 43-residue domain includes eight disulfide-linked cysteines and has been implicated in the binding of N-acetylglucosamine and its polymers. This study used 12 complementary DNA sequences and 1 amino acid sequence of proteins with one, two, and four copies of this domain to infer a 44-amino acid residue ancestor sequence for this domain, and to derive an evolutionary tree relating these domains in the different proteins. The tree relating these single-domain sequences is divided into two major branches, one consisting of the multidomain dimeric lectins, which we have earlier suggested arose by duplication of a single copy of the disulfide-rich domain, and the other branch consisting of the monomeric chitinases and wound-inducible proteins, which have a single copy of the domain fused to a larger polypeptide. Reference to the three-dimensional structure of WGA and its saccharide complexes shows that the saccharide-binding residues as well as cysteine and glycine residues are conserved among all available sequences. In contrast, many residues at the dimer interface of the domains of WGA are not conserved in those proteins with a single domain, implying that the aggregation state of the domains in these proteins differs from that of the gras lectins. Also, the base compositions of the four-domain and one-domain branches of the tree differ, indicating distinct selective pressures at the level of both protein structure and the gene or its transcript.
J Mol Evol 1991 Sep
PMID:Evolution of a family of N-acetylglucosamine binding proteins containing the disulfide-rich domain of wheat germ agglutinin. 175 99

Two new crystal forms (forms III and IV) have been grown of diphtheria toxin (DT), which kills susceptible cells by catalyzing the ADP-ribosylation of elongation factor 2, thereby stopping protein synthesis. Forms III and IV diffract to 2.3 A and 2.7 A resolution, respectively. Both forms belong to space group C2; the unit cell parameters for form III are a = 107.3 A, b = 91.7 A, c = 66.3 A and beta = 94.7 degrees and those for form IV are a = 108.3 A, b = 92.3 A, c = 66.1 A and beta = 90.4 degrees. Both forms have one protein chain per asymmetric unit with the dimeric molecule on a twofold axis of symmetry. Form IV is exceptional among all crystal forms of DT in that it can be grown reproducibly. Thus the form IV crystals should yield a crystallographic structure giving insight into the catalytic, receptor-binding and membrane-insertion properties of DT.
J Mol Biol 1991 Dec 20
PMID:Crystallization of diphtheria toxin. 176 53

The haploid genomes of all known primates have two or more adult alpha-globin genes contained within tandemly arranged duplication units. Although the tandem duplication event generating these alpha-globin loci is believed to occur prior to the divergence of primates, a number of length polymorphisms exist within the loci among different primate species. In order to understand the molecular basis of these length polymorphisms, we have cloned and determined the nucleotide sequence of a major portion of the rhesus monkey adult alpha-globin locus. Sequence comparison to human suggests that the length difference between the adult alpha-globin loci of human and Old World monkey is the result of one or more DNA recombination processes, all of which appeared to be related to the transposition of Alu family repeats. First, the finding of a monomeric Alu family repeat at the junction between nonhomology block I and homology block Y of the alpha 2 gene-containing unit in rhesus macaque suggests that the dimeric Alu family repeat, Alu 3, at the orthologous position in human was generated by insertion of a monomeric Alu family repeat into the 3' end of another preexisting Alu family repeat. Second, two Alu family repeats, Alu 1 and Alu 2, exist in human at the 3' end of each of the two X homology blocks, respectively. However, this pair of paralogous Alu family repeats is absent at the corresponding positions in rhesus macaques. This raises interesting questions regarding the evolutionary origin of Alu 1 and Alu 2. Finally, DNA sequences immediately downstream from the insertion site of Alu 2 are completely different between human and rhesus macaque.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Evol 1991 Dec
PMID:The adult alpha-globin locus of Old World monkeys: an abrupt breakdown of sequence similarity to human is defined by an Alu family repeat insertion site. 177 33


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