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Viruses Apr 2021HIV-1 (human immunodeficiency virus type 1) infection begins with the attachment of the virion to a host cell by its envelope glycoprotein (Env), which subsequently... (Review)
Review
HIV-1 (human immunodeficiency virus type 1) infection begins with the attachment of the virion to a host cell by its envelope glycoprotein (Env), which subsequently induces fusion of viral and cell membranes to allow viral entry. Upon binding to primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4), Env undergoes large conformational changes and unleashes its fusogenic potential to drive the membrane fusion. The structural biology of HIV-1 Env and its complexes with the cellular receptors not only has advanced our knowledge of the molecular mechanism of how HIV-1 enters the host cells but also provided a structural basis for the rational design of fusion inhibitors as potential antiviral therapeutics. In this review, we summarize our latest understanding of the HIV-1 membrane fusion process and discuss related therapeutic strategies to block viral entry.
Topics: Anti-Retroviral Agents; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Membrane Fusion; Virus Internalization
PubMed: 33922579
DOI: 10.3390/v13050735 -
Trends in Microbiology Oct 2019HIV-1 envelope glycoprotein [Env; trimeric (gp160) cleaved to (gp120/gp41)] attaches the virion to a susceptible cell and induces fusion of viral and cell membranes to... (Review)
Review
HIV-1 envelope glycoprotein [Env; trimeric (gp160) cleaved to (gp120/gp41)] attaches the virion to a susceptible cell and induces fusion of viral and cell membranes to initiate infection. It interacts with the primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4) to allow viral entry by triggering large structural rearrangements and unleashing the fusogenic potential of gp41 to induce membrane fusion. Recent advances in structural biology of HIV-1 Env and its complexes with the cellular receptors have revealed molecular details of HIV-1 entry and yielded new mechanistic insights. In this review, I summarize our latest understanding of the HIV-1 membrane fusion process and discuss possible pathways for productive viral entry.
Topics: CD4 Antigens; HIV Envelope Protein gp160; HIV Infections; HIV-1; Life Cycle Stages; Membrane Fusion; Models, Molecular; Protein Interaction Domains and Motifs; Receptors, CCR5; Receptors, CXCR4; Virus Internalization
PubMed: 31262533
DOI: 10.1016/j.tim.2019.06.002 -
Cold Spring Harbor Perspectives in... Oct 2021Hemagglutinins (HAs) are the receptor-binding and membrane fusion glycoproteins of influenza viruses. They recognize sialic acid-containing, cell-surface glycoconjugates... (Review)
Review
Hemagglutinins (HAs) are the receptor-binding and membrane fusion glycoproteins of influenza viruses. They recognize sialic acid-containing, cell-surface glycoconjugates as receptors but have limited affinity for them, and, as a consequence, virus attachment to cells requires their interaction with several virus HAs. Receptor-bound virus is transferred into endosomes where membrane fusion by HAs is activated at pH between 5 and 6.5, depending on the strain of virus. Fusion activity requires extensive rearrangements in HA conformation that include extrusion of a buried "fusion peptide" to connect with the endosomal membrane, form a bridge to the virus membrane, and eventually bring both membranes close together. In this review, we give an overview of the structures of the 16 genetically and antigenically distinct subtypes of influenza A HA in relation to these two functions in virus replication and in relation to recognition of HA by antibodies that neutralize infection.
Topics: Hemagglutinins; Humans; Hydrogen-Ion Concentration; Membrane Fusion; Orthomyxoviridae
PubMed: 32513673
DOI: 10.1101/cshperspect.a038638 -
Current Biology : CB Apr 2018A fundamental hallmark of eukaryotic cells is their compartmentalization into functionally distinct organelles, including those of the secretory and endocytic pathways.... (Review)
Review
A fundamental hallmark of eukaryotic cells is their compartmentalization into functionally distinct organelles, including those of the secretory and endocytic pathways. Transport of cargo between these compartments and to/from the cell surface is mediated by membrane-bound vesicles and tubules. Delivery of cargo is facilitated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated membrane fusion of vesicles with their target compartments. Vesicles contain a variety of cargos, including lipids, membrane proteins, signaling molecules, biosynthetic and hydrolytic enzymes, and the trafficking machinery itself. Proper function of membrane trafficking is required for cellular growth, division, movement, and cell-cell communication. Defects in these processes have been implicated in a variety of human diseases, such as cancer, diabetes, neurodegenerative disorders, ciliopathies, and infections. The elucidation of the mechanisms of SNARE assembly and disassembly is key to understanding how membrane fusion is regulated throughout eukaryotes. Here, we introduce the SNARE proteins, their structures and functions in eukaryotic cells, and discuss recent breakthroughs in elucidating the regulation of SNARE assembly and disassembly through the use of high-resolution structural biology and biophysical techniques.
Topics: Animals; Biological Transport; Cell Membrane; Humans; Membrane Fusion; Protein Binding; Protein Transport; SNARE Proteins
PubMed: 29689222
DOI: 10.1016/j.cub.2018.01.005 -
Current Biology : CB Apr 2018Exosomes and ectosomes, two distinct types of extracellular vesicles generated by all types of cell, play key roles in intercellular communication. The formation of... (Review)
Review
Exosomes and ectosomes, two distinct types of extracellular vesicles generated by all types of cell, play key roles in intercellular communication. The formation of these vesicles depends on local microdomains assembled in endocytic membranes for exosomes and in the plasma membrane for ectosomes. These microdomains govern the accumulation of proteins and various types of RNA associated with their cytosolic surface, followed by membrane budding inward for exosome precursors and outward for ectosomes. A fraction of endocytic cisternae filled with vesicles - multivesicular bodies - are later destined to undergo regulated exocytosis, leading to the extracellular release of exosomes. In contrast, the regulated release of ectosomes follows promptly after their generation. These two types of vesicle differ in size - 50-150 nm for exosomes and 100-500 nm for ectosomes - and in the mechanisms of assembly, composition, and regulation of release, albeit only partially. For both exosomes and ectosomes, the surface and luminal cargoes are heterogeneous when comparing vesicles released by different cell types or by single cells in different functional states. Upon release, the two types of vesicle navigate through extracellular fluid for varying times and distances. Subsequently, they interact with recognized target cells and undergo fusion with endocytic or plasma membranes, followed by integration of vesicle membranes into their fusion membranes and discharge of luminal cargoes into the cytosol, resulting in changes to cellular physiology. After fusion, exosome/ectosome components can be reassembled in new vesicles that are then recycled to other cells, activating effector networks. Extracellular vesicles also play critical roles in brain and heart diseases and in cancer, and are useful as biomarkers and in the development of innovative therapeutic approaches.
Topics: Animals; Cell Communication; Cell Membrane; Cell-Derived Microparticles; Exocytosis; Exosomes; Extracellular Vesicles; Humans; Membrane Fusion; Multivesicular Bodies; Signal Transduction
PubMed: 29689228
DOI: 10.1016/j.cub.2018.01.059 -
Annual Review of Virology Sep 2016The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell... (Review)
Review
The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors, leading to viral attachment. The spike protein exists in two structurally distinct conformations, prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered, leading to membrane fusion. This article reviews current knowledge about the structures and functions of coronavirus spike proteins, illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins, receptor recognition and membrane fusion, in the context of the corresponding functions from other viruses and host cells.
Topics: Coronavirus; Coronavirus Infections; Humans; Membrane Fusion; Membrane Glycoproteins; Receptors, Virus; Spike Glycoprotein, Coronavirus; Viral Envelope Proteins; Virus Attachment; Virus Internalization
PubMed: 27578435
DOI: 10.1146/annurev-virology-110615-042301 -
Autophagy Oct 2021Macroautophagy/autophagy refers to the engulfment of cellular contents selected for lysosomal degradation. The final step in autophagy is the fusion of autophagosome... (Review)
Review
Macroautophagy/autophagy refers to the engulfment of cellular contents selected for lysosomal degradation. The final step in autophagy is the fusion of autophagosome with the lysosome, which is mediated by SNARE proteins. Of the SNAREs, autophagosome-localized Q-SNAREs, such as STX17 and SNAP29, and lysosome-localized R-SNAREs, such as VAMP8 or VAMP7, have been reported to be involved. Recent studies also reveal participation of the R-SNARE, YKT6, in autophagosome-lysosome fusion. These SNAREs, with the help of other regulatory factors, act coordinately to spatiotemporally control the fusion process. Besides regulating autophagosome-lysosome fusion, some SNAREs, such as STX17, also function in other autophagic processes, including autophagosome formation and mitophagy. A better understanding of the functions of SNAREs will shed light on the molecular mechanisms of autophagosome-lysosome fusion as well as on the mechanisms by which autophagy is globally regulated.: ATG: autophagy related; DNM1L: dynamin 1 like; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor associated protein like 1; IRGM: immunity related GTPase M; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PLEKHM1: pleckstrin homology and RUN domain containing M1; PRKN: PRKN RBR E3 ubiquitin protein ligase; RAB2A: RAB2A, member RAS oncogene family; RAB33B: RAB33B, member RAS oncogene family; RAB7A: RAB7A, member RAS oncogene family; RB1CC1: RB1 inducible coiled-coil 1; RTN3: reticulon 3; RUBCNL: rubicon like autophagy enhancer; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNAP29: synaptosomal associated protein 29; STX17: syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1; VAMP7: vesicle associated membrane protein 7; VAMP8: vesicle associated membrane protein 8; YKT6: YKT6 v-SNARE homolog.
Topics: Autophagosomes; Autophagy; Lysosomes; Macroautophagy; Membrane Fusion; Qa-SNARE Proteins; R-SNARE Proteins; SNARE Proteins
PubMed: 32924745
DOI: 10.1080/15548627.2020.1823124 -
The Journal of Cell Biology Oct 2021Fertilization is defined as the union of two gametes. During fertilization, sperm and egg fuse to form a diploid zygote to initiate prenatal development. In mammals,... (Review)
Review
Fertilization is defined as the union of two gametes. During fertilization, sperm and egg fuse to form a diploid zygote to initiate prenatal development. In mammals, fertilization involves multiple ordered steps, including the acrosome reaction, zona pellucida penetration, sperm-egg attachment, and membrane fusion. Given the success of in vitro fertilization, one would think that the mechanisms of fertilization are understood; however, the precise details for many of the steps in fertilization remain a mystery. Recent studies using genetic knockout mouse models and structural biology are providing valuable insight into the molecular basis of sperm-egg attachment and fusion. Here, we review the cell biology of fertilization, specifically summarizing data from recent structural and functional studies that provide insights into the interactions involved in human gamete attachment and fusion.
Topics: Cell Biology; Fertilization; Humans; Membrane Fusion
PubMed: 34459848
DOI: 10.1083/jcb.202102146 -
Nature Communications Aug 2023The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of...
The delivery of genetic cargo remains one of the largest obstacles to the successful translation of experimental therapies, in large part due to the absence of targetable delivery vectors. Enveloped delivery modalities use viral envelope proteins, which determine tropism and induce membrane fusion. Here we develop DIRECTED (Delivery to Intended REcipient Cells Through Envelope Design), a modular platform that consists of separate fusion and targeting components. To achieve high modularity and programmable cell type specificity, we develop multiple strategies to recruit or immobilize antibodies on the viral envelope, including a chimeric antibody binding protein and a SNAP-tag enabling the use of antibodies or other proteins as targeting molecules. Moreover, we show that fusogens from multiple viral families are compatible with DIRECTED and that DIRECTED components can target multiple delivery chassis (e.g., lentivirus and MMLV gag) to specific cell types, including primary human T cells in PBMCs and whole blood.
Topics: Humans; Antibodies; Lentivirus; Membrane Fusion; Tropism; Viral Envelope Proteins
PubMed: 37612276
DOI: 10.1038/s41467-023-40788-8 -
Advances in Virus Research 2019The first steps in phage lysis involve a temporally controlled permeabilization of the cytoplasmic membrane followed by enzymatic degradation of the peptidoglycan. For... (Review)
Review
The first steps in phage lysis involve a temporally controlled permeabilization of the cytoplasmic membrane followed by enzymatic degradation of the peptidoglycan. For Caudovirales of Gram-negative hosts, there are two different systems: the holin-endolysin and pinholin-SAR endolysin pathways. In the former, lysis is initiated when the holin forms micron-scale holes in the inner membrane, releasing active endolysin into the periplasm to degrade the peptidoglycan. In the latter, lysis begins when the pinholin causes depolarization of the membrane, which activates the secreted SAR endolysin. Historically, the disruption of the first two barriers of the cell envelope was thought to be necessary and sufficient for lysis of Gram-negative hosts. However, recently a third functional class of lysis proteins, the spanins, has been shown to be required for outer membrane disruption. Spanins are so named because they form a protein bridge that connects both membranes. Most phages produce a two-component spanin complex, composed of an outer membrane lipoprotein (o-spanin) and an inner membrane protein (i-spanin) with a predominantly coiled-coil periplasmic domain. Some phages have a different type of spanin which spans the periplasm as a single molecule, by virtue of an N-terminal lipoprotein signal and a C-terminal transmembrane domain. Evidence is reviewed supporting a model in which the spanins function by fusing the inner membrane and outer membrane. Moreover, it is proposed that spanin function is inhibited by the meshwork of the peptidoglycan, thus coupling the spanin step to the first two steps mediated by the holin and endolysin.
Topics: Bacteriolysis; Bacteriophages; Cell Wall; DNA; Evolution, Molecular; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Viral; Gram-Negative Bacteria; Membrane Fusion; N-Acetylmuramoyl-L-alanine Amidase; Signal Transduction; Viral Proteins
PubMed: 30635077
DOI: 10.1016/bs.aivir.2018.09.003