scholarly journals Species-specific gamete recognition initiates fusion-driving trimer formation by conserved fusogen HAP2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jun Zhang ◽  
Jennifer F. Pinello ◽  
Ignacio Fernández ◽  
Eduard Baquero ◽  
Juliette Fedry ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Membrane Insertion ◽  
Structural Studies ◽  
Enveloped Viruses ◽  
Gamete Recognition ◽  
Membrane Attachment ◽  
Trimer Formation ◽  
Species Specific ◽  
Specific Membrane ◽  
Fusion Loop

AbstractRecognition and fusion between gametes during fertilization is an ancient process. Protein HAP2, recognized as the primordial eukaryotic gamete fusogen, is a structural homolog of viral class II fusion proteins. The mechanisms that regulate HAP2 function, and whether virus-fusion-like conformational changes are involved, however, have not been investigated. We report here that fusion between plus and minus gametes of the green alga Chlamydomonas indeed requires an obligate conformational rearrangement of HAP2 on minus gametes from a labile, prefusion form into the stable homotrimers observed in structural studies. Activation of HAP2 to undergo its fusogenic conformational change occurs only upon species-specific adhesion between the two gamete membranes. Following a molecular mechanism akin to fusion of enveloped viruses, the membrane insertion capacity of the fusion loop is required to couple formation of trimers to gamete fusion. Thus, species-specific membrane attachment is the gateway to fusion-driving HAP2 rearrangement into stable trimers.

scholarly journals Conformational rearrangements in the transmembrane domain of CNGA1 channels revealed by single-molecule force spectroscopy

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Sourav Maity ◽  
Monica Mazzolini ◽  
Manuel Arcangeletti ◽  
Alejandro Valbuena ◽  
Paolo Fabris ◽  
...  
Keyword(s):  
Single Molecule ◽  
Conformational Changes ◽  
Transmembrane Domain ◽  
Force Spectroscopy ◽  
Dynamic Structure ◽  
Transmembrane Domains ◽  
Structural Studies ◽  
Single Molecule Force Spectroscopy ◽  
Conformational Rearrangements ◽  
Α Helix

Abstract Cyclic nucleotide-gated (CNG) channels are activated by binding of cyclic nucleotides. Although structural studies have identified the channel pore and selectivity filter, conformation changes associated with gating remain poorly understood. Here we combine single-molecule force spectroscopy (SMFS) with mutagenesis, bioinformatics and electrophysiology to study conformational changes associated with gating. By expressing functional channels with SMFS fingerprints in Xenopus laevis oocytes, we were able to investigate gating of CNGA1 in a physiological-like membrane. Force spectra determined that the S4 transmembrane domain is mechanically coupled to S5 in the open state, but S3 in the closed state. We also show there are multiple pathways for the unfolding of the transmembrane domains, probably caused by a different degree of α-helix folding. This approach demonstrates that CNG transmembrane domains have dynamic structure and establishes SMFS as a tool for probing conformational change in ion channels.

scholarly journals How Melittin Inserts into Cell Membrane: Conformational Changes, Inter-Peptide Cooperation, and Disturbance on the Membrane

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1775 ◽  
Author(s):  
Jiajia Hong ◽  
Xuemei Lu ◽  
Zhixiong Deng ◽  
Shufeng Xiao ◽  
Bing Yuan ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Membrane Structure ◽  
Lipid Extraction ◽  
Immune Defense ◽  
Resistant Bacteria ◽  
Membrane Insertion ◽  
Free Energy Barrier ◽  
Surface Binding ◽  
Bacterial Killing ◽  
Bacterial Membranes

Antimicrobial peptides (AMPs), as a key component of the immune defense systems of organisms, are a promising solution to the serious threat of drug-resistant bacteria to public health. As one of the most representative and extensively studied AMPs, melittin has exceptional broad-spectrum activities against microorganisms, including both Gram-positive and Gram-negative bacteria. Unfortunately, the action mechanism of melittin with bacterial membranes, especially the underlying physics of peptide-induced membrane poration behaviors, is still poorly understood, which hampers efforts to develop melittin-based drugs or agents for clinical applications. In this mini-review, we focus on recent advances with respect to the membrane insertion behavior of melittin mostly from a computational aspect. Membrane insertion is a prerequisite and key step for forming transmembrane pores and bacterial killing by melittin, whose occurrence is based on overcoming a high free-energy barrier during the transition of melittin molecules from a membrane surface-binding state to a transmembrane-inserting state. Here, intriguing simulation results on such transition are highlighted from both kinetic and thermodynamic aspects. The conformational changes and inter-peptide cooperation of melittin molecules, as well as melittin-induced disturbances to membrane structure, such as deformation and lipid extraction, are regarded as key factors influencing the insertion of peptides into membranes. The associated intermediate states in peptide conformations, lipid arrangements, membrane structure, and mechanical properties during this process are specifically discussed. Finally, potential strategies for enhancing the poration ability and improving the antimicrobial performance of AMPs are included as well.

scholarly journals Exploring lectin–glycan interactions to combat COVID-19: Lessons acquired from other enveloped viruses

Glycobiology ◽  
2020 ◽  
Author(s):  
Luís Cláudio Nascimento da Silva ◽  
Juliana Silva Pereira Mendonça ◽  
Weslley Felix de Oliveira ◽  
Karla Lílian Rodrigues Batista ◽  
Adrielle Zagmignan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Whole Blood ◽  
Therapeutic Approach ◽  
Viral Infections ◽  
Viral Envelope ◽  
Structural Studies ◽  
Human Coronavirus ◽  
Enveloped Viruses ◽  
Wide Range ◽  
Great Pressure

Abstract The emergence of a new human coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed great pressure on the health system worldwide. The presence of glycoproteins on the viral envelope opens a wide range of possibilities for the application of lectins to address some urgent problems involved in this pandemic. In this work, we discuss the potential contributions of lectins from nonmammalian sources in the development of several fields associated with viral infections, most notably COVID-19. We review the literature on the use of nonmammalian lectins as a therapeutic approach against members of the Coronaviridae family, including recent advances in strategies of protein engineering to improve their efficacy. The applications of lectins as adjuvants for antiviral vaccines are also discussed. Finally, we present some emerging strategies employing lectins for the development of biosensors, microarrays, immunoassays and tools for purification of viruses from whole blood. Altogether, the data compiled in this review highlight the importance of structural studies aiming to improve our knowledge about the basis of glycan recognition by lectins and its repercussions in several fields, providing potential solutions for complex aspects that are emerging from different health challenges.

Investigating extracellular in situ EGFR structure and conformational changes using FRET microscopy

2012 ◽  
Vol 40 (1) ◽  
pp. 189-194 ◽  
Author(s):  
Selene K. Roberts ◽  
Christopher J. Tynan ◽  
Martyn Winn ◽  
Marisa L. Martin-Fernandez
Keyword(s):  
Growth Factor ◽  
Experimental Evidence ◽  
Conformational Changes ◽  
Structural Models ◽  
Structural Studies ◽  
Receptor Dimerization ◽  
Factor Binding ◽  
Full Picture ◽  
Crystallographic Structures

The crystallographic structures of functional fragments of ErbBs have provided excellent insights into the geometry of growth factor binding and receptor dimerization. By placing together receptor fragments to build structural models of entire receptors, we expect to understand how these enzymes are allosterically regulated; however, several predictions from these models are inconsistent with experimental evidence from cells. The opening of this gap underlines the need to investigate intact ErbBs by combining cellular and structural studies into a full picture.

scholarly journals Antibody Binding in Proximity to the Receptor/Glycoprotein Complex Leads to a Basal Level of Virus Neutralization

2007 ◽  
Vol 81 (16) ◽  
pp. 8809-8813 ◽  
Author(s):  
Xinzhen Yang ◽  
Inna Lipchina ◽  
Michelle Lifton ◽  
Liping Wang ◽  
Joseph Sodroski
Keyword(s):  
Conformational Changes ◽  
Steric Hindrance ◽  
Virus Entry ◽  
Receptor Protein ◽  
Receptor Complex ◽  
Retroviral Infection ◽  
Enveloped Viruses ◽  
Glycoprotein Complex ◽  
Additional Support ◽  
Avian Sarcoma

ABSTRACT Hypothetically, antibodies may neutralize enveloped viruses by diverse mechanisms, such as disruption of receptor binding, interference with conformational changes required for virus entry, steric hindrance, or virus aggregation. Here, we demonstrate that retroviral infection mediated by the avian sarcoma-leukosis virus (ASLV-A) envelope glycoproteins can be neutralized by an antibody directed against a functionally unimportant component of a chimeric receptor protein. Thus, the binding of an antibody in proximity to the retroviral envelope glycoprotein-receptor complex, without binding to the entry machinery itself, results in neutralization. This finding provides additional support for the hypothesis that steric hindrance is sufficient for antibody-mediated neutralization of retroviruses.

scholarly journals Molecular mechanisms of substrate-controlled ring dynamics and sub-stepping in a nucleic-acid dependent hexameric motor

2016 ◽  
Author(s):  
Nathan D. Thomsen ◽  
Michael R. Lawson ◽  
Lea B. Witkowsky ◽  
Song Qu ◽  
James M. Berger
Keyword(s):  
Nucleic Acid ◽  
Conformational Changes ◽  
Molecular Motors ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Atp Hydrolysis ◽  
Ring Closure ◽  
Structural Studies ◽  
Saxs Data ◽  
Structural Methods

ABSTRACTRing-shaped hexameric helicases and translocases support essential DNA, RNA, and protein-dependent transactions in all cells and many viruses. How such systems coordinate ATPase activity between multiple subunits to power conformational changes that drive the engagement and movement of client substrates is a fundamental question. Using the E. coli Rho transcription termination factor as a model system, we have employed solution and crystallographic structural methods to delineate the range of conformational changes that accompany distinct substrate and nucleotide cofactor binding events. SAXS data show that Rho preferentially adopts an open-ring state in solution, and that RNA and ATP are both required to cooperatively promote ring closure. Multiple closed-ring structures with different RNA substrates and nucleotide occupancies capture distinct catalytic intermediates accessed during translocation. Our data reveal how RNA-induced ring closure templates a sequential ATP-hydrolysis mechanism, provide a molecular rationale for how the Rho ATPase domains distinguishes between distinct RNA sequences, and establish the first structural snapshots of substepping events in a hexameric helicase/translocase.SIGNIFICANCEHexameric, ring-shaped translocases are molecular motors that convert the chemical energy of ATP hydrolysis into the physical movement of protein and nucleic acid substrates. Structural studies of several distinct hexameric translocases have provided insights into how substrates are loaded and translocated; however, the range of structural changes required for coupling ATP turnover to a full cycle of substrate loading and translocation has not been visualized for any one system. Here, we combine low-and high-resolution structural studies of the Rho helicase, defining for the first time the ensemble of conformational transitions required both for substrate loading in solution and for substrate movement by a processive hexameric translocase.

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