Showing papers by "Howard Hughes Medical Institute published in 1990"
TL;DR: Staphylococcal enterotoxins and a group of related proteins made by Streptococci cause food poisoning and shock in man and animals and it is likely that some or all of the pathological effects of these toxins are caused by their ability to activate quickly so many T cells.
Abstract: Staphylococcal enterotoxins and a group of related proteins made by Streptococci cause food poisoning and shock in man and animals. These proteins share an ability to bind to human and mouse major histocompatibility complex proteins. The complex ligand so formed has specificity for a particular part of T cell receptors, V beta, and by engaging V beta can stimulate many T cells. It is likely that some or all of the pathological effects of these toxins are caused by their ability to activate quickly so many T cells. It is also possible that encounters with such toxins have caused mice, at least, to evolve mechanisms for varying their T cell V beta repertoires, such that they are less susceptible to attack by the toxins.
1,941 citations
TL;DR: It is reported that cultured hippocampal astrocytes can respond to glutamate with a prompt and oscillatory elevation of cytoplasmic free calcium, visible through use of the fluorescent calcium indicator fluo-3.
Abstract: The finding that astrocytes possess glutamate-sensitive ion channels hinted at a previously unrecognized signaling role for these cells. Now it is reported that cultured hippocampal astrocytes can respond to glutamate with a prompt and oscillatory elevation of cytoplasmic free calcium, visible through use of the fluorescent calcium indicator fluo-3. Two types of glutamate receptor--one preferring quisqualate and releasing calcium from intracellular stores and the other preferring kainate and promoting surface-membrane calcium influx--appear to be involved. Moreover, glutamate-induced increases in cytoplasmic free calcium frequently propagate as waves within the cytoplasm of individual astrocytes and between adjacent astrocytes in confluent cultures. These propagating waves of calcium suggest that networks of astrocytes may constitute a long-range signaling system within the brain.
1,829 citations
TL;DR: In vivo administration of SCF can reverse the macrocytic anemia and locally repair the mast cell deficiency of Sl/Sld mice and provide biological and physical evidence that SCF is a ligand for the c-kit receptor.
1,485 citations
TL;DR: The molecular mechanisms underlying rapid βAR desensitization do not appear to require internalization of the receptors, but rather an alteration in the functioning of βAR themselves that uncouples the receptors from the stimulatory G protein Gs.
Abstract: Cellular responses to many hormones and neurotransmitters wane rapidly despite continuous exposure of cells to these stimuli. This phenomenon, termed desensitization, has been particularly well studied for the stimulation of cAMP levels by plasma membrane beta-adrenergic receptors (beta AR). The molecular mechanisms underlying rapid beta AR desensitization do not appear to require internalization of the receptors, but rather an alteration in the functioning of beta AR themselves that uncouples the receptors from the stimulatory G protein Gs. This uncoupling phenomenon involves phosphorylation of beta AR by at least two kinases, PKA and the beta AR kinase (beta ARK), which are activated under different desensitizing conditions. Receptor phosphorylation by the two kinases leads to desensitization of the receptor response via distinct biochemical mechanisms, and additional cytosolic factors appear to be involved in the case of beta ARK. Numerous experimental approaches have been used recently to elucidate th...
1,286 citations
TL;DR: Identification of two unique mutations within cardiac MHC genes in all individuals with FHC from two unrelated families demonstrates that defects in the cardiac M HC genes can cause this disease.
1,264 citations
TL;DR: Evidence is presented that the glucocorticoid receptor (GR) and transcription factor Jun/AP-1 can reciprocally repress one another's transcriptional activation by a novel mechanism that is independent of DNA binding.
1,241 citations
TL;DR: K, a hematopoietic growth factor obtained from conditioned medium of BALB/c 3T3 fibroblasts that stimulates the proliferation of mast cells and early erythroid progenitors, specifically binds to the c-kit receptor.
1,201 citations
TL;DR: It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors.
Abstract: Homologous or agonist-specific desensitization of beta-adrenergic receptors is thought to be mediated by a specific kinase, the beta-adrenergic receptor kinase (beta ARK). However, recent data suggest that a cofactor is required for this kinase to inhibit receptor function. The complementary DNA for such a cofactor was cloned and found to encode a 418-amino acid protein homologous to the retinal protein arrestin. The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors.
1,185 citations
TL;DR: Observations indicate that the cycling of per-encoded protein could result from per RNA cycling, and that there is a feedback loop through which the activity of each per gene product causes cycling of its own RNA.
Abstract: Mutations in the period (per) gene of Drosophila melanogaster affect both circadian and ultradian rhythms. Levels of per gene product undergo circadian oscillation, and it is now shown that there is an underlying oscillation in the level of per RNA. The observations indicate that the cycling of per-encoded protein could result from per RNA cycling, and that there is a feedback loop through which the activity of per-encoded protein causes cycling of its own RNA.
1,054 citations
TL;DR: Data indicate that recombinant selenomethionyl proteins analyzed by MAD phasing offer a rather general means for the elucidation of atomic structures.
Abstract: An expression system has been established for the incorporation of selenomethionine into recombinant proteins produced from plasmids in Escherichia coli. Replacement of methionine by selenomethionine is demonstrated at the level of 100% for both T4 and E. coli thioredoxins. The natural recombinant proteins and the selenomethionyl variants of both thioredoxins crystallize isomorphously. Anomalous scattering factors were deduced from synchrotron X-ray absorption measurements of crystals of the selenomethionyl proteins. Taken with reference to experience in the structural analysis of selenobiotinyl streptavidin by the method of multiwavelength anomalous diffraction (MAD), these data indicate that recombinant selenomethionyl proteins analyzed by MAD phasing offer a rather general means for the elucidation of atomic structures.
1,042 citations
TL;DR: It is suggested that the H19 RNA, which is transcribed by RNA polymerase II and is spliced and polyadenylated, is not a classical mRNA but may be an RNA molecule.
Abstract: The mouse H19 gene was identified as an abundant hepatic fetal-specific mRNA under the transcriptional control of a trans-acting locus termed raf. The protein this gene encoded was not apparent from an analysis of its nucleotide sequence, since the mRNA contained multiple translation termination signals in all three reading frames. As a means of assessing which of the 35 small open reading frames might be important to the function of the gene, the human H19 gene was cloned and sequenced. Comparison of the two homologs revealed no conserved open reading frame. Cellular fractionation showed that H19 RNA is cytoplasmic but not associated with the translational machinery. Instead, it is located in a particle with a sedimentation coefficient of approximately 28S. Despite the fact that it is transcribed by RNA polymerase II and is spliced and polyadenylated, we suggest that the H19 RNA is not a classical mRNA. Instead, the product of this unusual gene may be an RNA molecule.
TL;DR: These findings strongly suggest that the TBR gene is the NF1 gene, and a number of cDNA clones from the translocation breakpoint region (TBR), one of which hybridizes to an approximately 11 kb mRNA.
TL;DR: It is shown that four glycoproteins are integral components of the dystrophin complex and that the concentration of one of these is greatly reduced in DMD patients, suggesting the reduction in this glycoprotein may be one of the first stages of the molecular pathogenesis of muscular dystrophy.
Abstract: Dystrophin, the protein encoded by the Duchenne muscular dystrophy (DMD) gene, exists in a large oligomeric complex. We show here that four glycoproteins are integral components of the dystrophin complex and that the concentration of one of these is greatly reduced in DMD patients. Thus, the absence of dystrophin may lead to the loss of a dystrophin-associated glycoprotein, and the reduction in this glycoprotein may be one of the first stages of the molecular pathogenesis of muscular dystrophy.
TL;DR: The function of int–1 in the mouse is explored by disrupting one of the two int-1 alleles in mouse embryo-derived stem cells using positive–negative selection and generating a chimaeric mouse that transmitted the mutant allele to its progeny.
Abstract: The int-1 proto-oncogene was first identified as a gene activated in virally induced mouse mammary tumours. Expression studies, however, suggest that the normal function of this gene may be in spermatogenesis and in the development of the central nervous system. Genes sharing sequence similarity with int-1 have been found throughout the animal kingdom. For example, int-1 has 54% amino-acid identity to the Drosophila segment polarity gene wingless (wg). Both the int-1 and wg gene products seem to be secreted proteins, presumably involved in cell-cell signalling. We have now explored the function of int-1 in the mouse by disrupting one of the two int-1 alleles in mouse embryo-derived stem cells using positive-negative selection. This cell line was used to generate a chimaeric mouse that transmitted the mutant allele to its progeny. Mice heterozygous for the int-1 null mutation are normal and fertile, whereas mice homozygous for the mutation may exhibit a range of phenotypes from death before birth to survival with severe ataxia. The latter pathology in mice and humans is often associated with defects in the cerebellum. Examination of int-1-/int-1- mice at several stages of embryogenesis revealed severe abnormalities in the development of the mesencephalon and metencephalon indicating a prominent role for the int-1 protein is in the induction of the mesencephalon and cerebellum.
TL;DR: Mouse chimeras derived from embryonic stem cells with a disrupted beta 2M gene transmitted the inactivated gene to their progeny and these animals are grossly deficient in CD4- CD8+ T cells, which normally mediate cytotoxic T cell function.
Abstract: Major histocompatibility class I proteins display viral and self antigens to potentially responsive cells and are important for the maturation of T cells; beta 2-microglobulin (beta 2M) is required for their normal expression. Mouse chimeras derived from embryonic stem cells with a disrupted beta 2M gene transmitted the inactivated gene to their progeny. Animals homozygous for the mutated beta 2M gene were obtained at expected frequencies after further breeding. The homozygotes appeared normal, although no class I antigens could be detected on their cells and the animals are grossly deficient in CD4- CD8+ T cells, which normally mediate cytotoxic T cell function.
TL;DR: The isolation and characterization of cDNAs and genes for these glucose transporters will facilitate studies of their role in the pathogenesis of disorders characterized by abnormal glucose transport, including diabetes mellitus, the glucose-galactose malabsorption syndrome, and benign renal glycosuria.
Abstract: The oxidation of glucose represents a major source of metabolic energy for mammaliancells However, because the plasma membrane is impermeable to polar molecules such as glucose, the cellular uptake of this important nutrient is accomplished by membrane-associated carrier proteins that bind and transfer it across the lipid bilayer Two classes of glucose carriers have been described in mammalian cells: the Na+-glucose cotransporter and the facilitative glucose transporter The Na+-glucose cotransporter transports glucose against its concentration gradient by coupling its uptake with the uptake of Na+ that is being transported down its concentration gradient Facilitative glucose c rriers accelerate the transport of glucose down its concentration gradient by facilitative diffusion, a form of passive transport cDNAs have been isolated from human tissues encoding a Na+-glucose-cotransporter protein and five functional facilitative glucosetransporter isoforms The Na+-glucose cotransporter is expressed by absorptive epithelial cells of the small intestine and is involved in the dietary uptake of glucose The same or a related protein may be responsible for the reabsorption of glucose by the kidney Facilitative glucose carriers are expressed by most if not all cells The facilitative glucose-transporter isoforms have distinct tissue distributions and biochemical properties and contribute to the precise disposal of glucose under varying physiological conditions The GLUT1 (erythrocyte) and GLUT3 (brain) facilitative glucose-transporter isoforms may be responsible for basal or constitutive glucose uptake The GLUT2 (liver) isoform mediates the bidirectional transport of glucose by the hepatocyte and is responsible, at least in part, for the movement of glucose out of absorptive epithelial cells into the circulation in the small intestine and kidney This isoform may also comprise part of the glucosesensing mechanism of the insulin-producing β-cell The subcellular localization of the GLUT4 (muscle/fat) isoform changes in response to insulin, and this isoform is responsible for most of the insulin-stimulated uptake of glucose that occurs in muscle and adipose tissue The GLLJT5 (small intestine) facilitative glucose-transporter isoform is expressed at highest levels in the small intestine and may be involved in the transcellular transport of glucose by absorptive epithelial cells The exon-intron organizations of the human GLUT1 , GLUT2 , and GLUT4 genes have been determined In addition, the chromosomal locations of the genes encoding the Na+-dependent and facilitative glucose carriers have been determined Restriction-fragment-length polymorphisms have also been identified at several of these loci The isolation and characterization of cDNAs and genes for these glucose transporters will facilitate studies of their role in the pathogenesis of disorders characterized by abnormal glucose transport, including diabetes mellitus, the glucose-galactose malabsorption syndrome, and benign renal glycosuria
TL;DR: It is demonstrated that a particular heat shock protein plays a critical role in cell survival at extreme temperatures and is rescued with the wild-type gene.
Abstract: A heat shock protein gene, HSP104, was isolated from Saccharomyces cerevisiae and a deletion mutation was introduced into yeast cells. Mutant cells grew at the same rate as wild-type cells and died at the same rate when exposed directly to high temperatures. However, when given a mild pre-heat treatment, the mutant cells did not acquire tolerance to heat, as did wild-type cells. Transformation with the wild-type gene rescued the defect of mutant cells. The results demonstrate that a particular heat shock protein plays a critical role in cell survival at extreme temperatures.
TL;DR: The Tetrahymena INTRON is described as a “spatially aggregating force” that “brings together the determinants of infectious disease and infectious disease in a synergistic manner”.
Abstract: PERSPECTlVES . ... . .... .. ..... ... . . ........ . .... ...... .... . ... 543 REACTION PATHWAY ... . . ... ...... . ....... .. ..... . ... . ..... .. . . ...... ... . . . 545 Splicing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545 Intron Cyclization . . . . . . ... . . . . . . .... . . . . . . . . . . . . ... . . . . . . . . . . . . . ... . ... .. . . . . . . . . . . . .. ... .. . . . . . . . 547 Splice SIte Hydrolysis ... ..... .. ...... . . ... ...... . . .. ...... . ... .... ... .. . 547 GROUP I INTRON STRUCTURE ....... . . ..... ....... ... ... . . 547 Secondary Structure and the Catalytic Core . . . .. . .. ..... . . . . .. . . . . . .. .. . .. . . . . . . . . . . . .. . . . . 548 Choosing the Reaction Sites . . . . . . . . . . . _ _ . . _ ..... . . . .... . _ . . . ... . . . ... . . . . . ... . . _ . . 550 G-Binding Site 552 Tertiary Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . . .... . . . .. . . . . . . . 555 ENZYMATlC REACTIONS OF THE Tetrahymena INTRON . . . ........ ..... . .. 556 CHEMISTR Y .. . ... . .... . . . .... . ... . ... . . . ...... . .. . . . ... . . . ..... .... . .. . . ... 558 ReversibUiry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558 Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559 Metal Ion Requirements 559 Competitive Inhibition by Arginine 560 PROTEIN FACILITATION ....... ... .. . . ... .. .. .. . . . . . . ..... . 561 INTRON MOBILITY ..... ... .... . .... . . .. . . . ..... .. . .... .... . ... . . ...... . ... . . ... ...... . . . .. . . . .. . . . 563
TL;DR: Binding was not detected on 3T3 fibroblasts carrying the steel (Sl) mutation, confirming the biological significance of the binding activity and demonstrating that mutations at the Sl locus affect the expression or structure of the kit ligand.
TL;DR: This work has taken advantage of the capacity of mammalian steroid receptors to function in yeast and constructed a strain of Saccharomyces cerevisiae in which hsp90 expression was regulatable and could be reduced more than 20-fold relative to wild type, providing the first biological evidence that hSp90 acts in the signal transduction pathway for steroid receptors.
Abstract: Signalling by steroid hormones is mediated by receptor proteins that bind hormonal ligands and regulate the transcription of specific genes. The heat-shock protein hsp90 seems to associate selectively with unliganded receptors (aporeceptors), but it has not been determined whether this interaction affects receptor function in vivo. To address the role of hsp90, we have taken advantage of the capacity of mammalian steroid receptors to function in yeast. We constructed a strain of Saccharomyces cerevisiae in which hsp90 expression was regulatable and could be reduced more than 20-fold relative to wild type. At low levels of hsp90, aporeceptors seem to be mostly hsp90-free, yet fail to enhance transcription; on hormone addition, the receptors are activated but with markedly reduced efficiency. Thus hsp90 does not inhibit receptor function solely by steric interference; rather, hsp90 seems to facilitate the subsequent response of the aporeceptor to the hormonal signal. This is the first biological evidence that hsp90 acts in the signal transduction pathway for steroid receptors.
TL;DR: The DNA binding subunit of the transcription factor NF-kappa B, p50, has been cloned and sequence analysis reveals remarkable homology for over 300 amino acids at the amino-terminal end to the oncogene v-rel, its cellular homolog c-rel and the Drosophila maternal effect gene dorsal as mentioned in this paper.
TL;DR: In this article, a set of proteins, including one with properties similar to mammalian CREBPs, that specifically bind the mammalian CRE sequence were found to be required for long-term facilitation.
Abstract: IN both vertebrates and invertebrates, long-term memory differs from short-term in requiring protein synthesis during training1,2. Studies of the gill and siphon withdrawal reflex in Aplysia indicate that similar requirements can be demonstrated at the level of sensory and motor neurons which may participate in memory storage. A single application of serotonin3, a transmitter that mediates sensitization, to individual sensory and motor cells in dissociated cell cultures leads to enhanced transmitter release from the sensory neurons that is independent of new macromolecular synthesis. Five applications of serotonin cause a long-term enhancement, lasting one or more days, which requires translation and transcription2,3. Prolonged application or intracellular injection into the sensory neuron of cyclic AMP, a second messenger for the action of serotonin, also produce long-term increases in synaptic strength4,5, suggesting that some of the gene products important for long-term facilitation are cAMP-inducible. In eukaryotic cells, most cAMP-inducible genes so far studied are activated by the cAMP-dependent protein kinase (A kinase), which phosphorylates transcription factors that bind the cAMP-responsive element TGACGTCA. The cAMP-responsive element (CRE) binds a protein dimer of relative molecular mass 43,000, the CRE-binding protein (CREBP), which has been purified and shown to increase transcription when phosphorylated by the A kinase6–11. Here we show that extracts of the Aplysia central nervous system and extracts of sensory neurons contain a set of proteins, including one with properties similar to mammalian CREBPs, that specifically bind the mammalian CRE sequence. Microinjection of the CRE sequence into the nucleus of a sensory neuron selectively blocks the serotonin-induced long-term increase in synaptic strength, without affecting short-term facilitation. Taken together, these observations suggest that one or more CREB-like transcriptional activators are required for long-term facilitation.
TL;DR: Exposure of CFTR to cultured cystic fibrosis airway epithelial cells corrected the Cl− channel defect, demonstrating a causal relationship between mutations in the CFTR gene and defective Cl− transport which is the hallmark of the disease.
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in cultured cystic fibrosis airway epithelial cells and Cl- channel activation assessed in single cells using a fluorescence microscopic assay and the patch-clamp technique. Expression of CFTR, but not of a mutant form of CFTR (delta F508), corrected the Cl- channel defect. Correction of the phenotypic defect demonstrates a causal relationship between mutations in the CFTR gene and defective Cl- transport which is the hallmark of the disease.
TL;DR: It is shown that Notch and Delta can associate within the membrane of a single cell, and further, that they form detergent-soluble intermolecular complexes.
TL;DR: Transient or stable expression of the cloned gene in host cells established specific ligand binding and functional activity characteristic of a D1 dopamine receptor coupled to stimulation of adenylyl cyclase.
Abstract: The diverse physiological actions of dopamine are mediated by its interaction with two basic types of G protein-coupled receptor, D1 and D2, which stimulate and inhibit, respectively, the enzyme adenylyl cyclase. Alterations in the number or activity of these receptors may be a contributory factor in diseases such as Parkinson's disease and schizophrenia. Here we describe the isolation and characterization of the gene encoding a human D1 dopamine receptor. The coding region of this gene is intronless, unlike the gene encoding the D2 dopamine receptor. The D1 receptor gene encodes a protein of 446 amino acids having a predicted relative molecular mass of 49,300 and a transmembrane topology similar to that of other G protein-coupled receptors. Transient or stable expression of the cloned gene in host cells established specific ligand binding and functional activity characteristic of a D1 dopamine receptor coupled to stimulation of adenylyl cyclase. Northern blot analysis and in situ hybridization revealed that the messenger RNA for this receptor is most abundant in caudate, nucleus accumbens and olfactory tubercle, with little or no mRNA detectable in substantia nigra, liver, kidney, or heart. Several observations from this work in conjunction with results from other studies are consistent with the idea that other D1 dopamine receptor subtypes may exist.
TL;DR: This article will review some important aspects of the biology of terminal differentiation in vivo and in vitro, and highlight the recent advances in elucidating the molecular mechanism underlying these processes.
Abstract: N the past ten years, there have been a number of major scientific discoveries in the field of epidermal differentiation. We owe many of these findings to the development of model tissue culture systems, and to technological advances in molecular biology. In this article, I will review some important aspects of the biology of terminal differentiation in vivo and in vitro, and highlight the recent advances in elucidating the molecular mechanism underlying these processes.
TL;DR: Experiments analysing the statistical properties of synaptic transmission, before and after the induction of long-term potentiation (LTP), suggest that expression of LTP largely arises in a presynaptic mechanism with an increased probability of transmitter release.
Abstract: Experiments analysing the statistical properties of synaptic transmission, before and after the induction of long-term potentiation (LTP), suggest that expression of LTP largely arises in a presynaptic mechanism--an increased probability of transmitter release.
TL;DR: It is demonstrated how polymorphism creates and alters subsites (pockets) positioned to bind peptide side chains, thereby suggesting the structural basis for allelic specificity in foreign antigen binding.
Abstract: We have determined the structure of a second human histocompati-bility glycoprotein, HLA-Aw68, by X-ray crystallography and refined it to a resolution of 2.6 A. Overall, the structure is extremely similar to that of HLA-A2 (refs 1, 2; and M.A.S. et al., manuscript in preparation), although the 11 amino-acid substitutions at polymorphic residues in the antigen-binding cleft alter the detailed shape and electrostatic charge of that site. A prominent negatively charged pocket within the cleft extends underneath the α-helix of the α_1-domain, providing a potential subsite for recognizing a positively charged side chain or peptide N terminus. Uninterpreted electron density, presumably representing an unknown 'antigen(s)', which seems to be different from that seen in the HLA-A2 structure, occupies the cleft and extends into the negatively charged pocket in HLA-Aw68. The structures of HLA-Aw68 and HLA-A2 demonstrate how polymorphism creates and alters subsites (pockets) positioned to bind peptide side chains, thereby suggesting the structural basis for allelic specificity in foreign antigen binding.
TL;DR: Using oligonucleotide primer sequences that can be used to amplify eight exons plus the muscle promoter of the dystrophin gene in a single multiplex polymerase chain reaction (PCR) will allow deletion detection and prenatal diagnosis for most DMD/BMD patients in a fraction of the time required for Southern blot analysis.
Abstract: We describe oligonucleotide primer sequences that can be used to amplify eight exons plus the muscle promoter of the dystrophin gene in a single multiplex polymerase chain reaction (PCR). When used in conjunction with an existing primer set, these two multiplex reactions detect about 98% of deletions in patients with Duchenne or Becker muscular dystrophy (DMD, BMD). Furthermore, these primers amplify most of the exons in the deletion prone “hot spot” region around exons 44 to 53, allowing determination of deletion endpoints and prediction of mutational effects on the translational reading frame. Thus, use of these PCR-based assays will allow deletion detection and prenatal diagnosis for most DMD/BMD patients in a fraction of the time required for Southern blot analysis.
TL;DR: The CD4 antigen is the high affinity cellular receptor for the human immunodeficiency virus type-1 (HIV-1).
Abstract: The CD4 antigen is the high affinity cellular receptor for the human immunodeficiency virus type-1 (HIV-1). Binding of recombinant soluble CD4 (sCD4) or the purified V1 domain of sCD4 to the surface glycoprotein gp120 on virions resulted in rapid dissociation of gp120 from its complex with the transmembrane glycoprotein gp41. This may represent the initial stage in virus-cell and cell-cell fusion. Shedding of gp120 from virions induced by sCD4 may also contribute to the mechanism by which these soluble receptor molecules neutralize HIV-1.