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Article: Crystal structure of an inulosucrase from Halalkalicoccus jeotgali B3T, a halophilic archaeal strain

Ghauri, Komal / Pijning, Tjaard / Munawar, Nayla / Ali, Hazrat / Ghauri, Muhammad A. / Anwar, Munir A. / Wallis, Russell

FEBS journal. 2021 Oct., v. 288, no. 19

2021

Abstract: Several archaea harbor genes that code for fructosyltransferase (FTF) enzymes. These enzymes have not been characterized yet at structure–function level, but are of extreme interest in view of their potential role in the synthesis of novel compounds for ... ...

Abstract	Several archaea harbor genes that code for fructosyltransferase (FTF) enzymes. These enzymes have not been characterized yet at structure–function level, but are of extreme interest in view of their potential role in the synthesis of novel compounds for food, nutrition, and pharmaceutical applications. In this study, 3D structure of an inulin‐type fructan producing enzyme, inulosucrase (InuHj), from the archaeon Halalkalicoccus jeotgali was resolved in its apo form and with bound substrate (sucrose) molecule and first transglycosylation product (1‐kestose). This is the first crystal structure of an FTF from halophilic archaea. Its overall five‐bladed β‐propeller fold is conserved with previously reported FTFs, but also shows some unique features. The InuHj structure is closer to those of Gram‐negative bacteria, with exceptions such as residue E266, which is conserved in FTFs of Gram‐positive bacteria and has possible role in fructan polymer synthesis in these bacteria as compared to fructooligosaccharide (FOS) production by FTFs of Gram‐negative bacteria. Highly negative electrostatic surface potential of InuHj, due to a large amount of acidic residues, likely contributes to its halophilicity. The complex of InuHj with 1‐kestose indicates that the residues D287 in the 4B‐4C loop, Y330 in 4D‐5A, and D361 in the unique α2 helix may interact with longer FOSs and facilitate the binding of longer FOS chains during synthesis. The outcome of this work will provide targets for future structure–function studies of FTF enzymes, particularly those from archaea.
Keywords	Archaea ; crystal structure ; fructans ; fructooligosaccharides ; glycosylation ; nutrition ; polymers ; sucrose
Language	English
Dates of publication	2021-10
Size	p. 5723-5736.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15843
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Interactions of Candida tropicalis pH-related antigen 1 with complement proteins C3, C3b, factor-H, C4BP and complement evasion.

Valand, Nisha / Gazioglu, Ozcan / Yesilkaya, Hasan / Shivkumar, Maitreyi / Horley, Neill / Arroo, Randolph / Wallis, Russell / Kishore, Uday / Venkatraman Girija, Umakhanth

Immunobiology

2022 Volume 228, Issue 1, Page(s) 152303

Abstract: Candida, as a part of the human microbiota, can cause opportunistic infections that are either localised or systemic candidiasis. Emerging resistance to the standard antifungal drugs is associated with increased mortality rate due to invasive Candida ... ...

Abstract	Candida, as a part of the human microbiota, can cause opportunistic infections that are either localised or systemic candidiasis. Emerging resistance to the standard antifungal drugs is associated with increased mortality rate due to invasive Candida infections, particularly in immunocompromised patients. While there are several species of Candida, an increasing number of Candida tropicalis isolates have been recently reported from patients with invasive candidiasis or inflammatory bowel diseases. In order to establish infections, C. tropicalis has to adopt several strategies to escape the host immune attack. Understanding the immune evasion strategies is of great importance as these can be exploited as novel therapeutic targets. C. albicans pH-related antigen 1 (CaPra1), a surface bound and secretory protein, has been found to interact strongly with the immune system and help in complement evasion. However, the role of C. tropicalis Pra1 (CtPra1) and its interaction with the complement is not studied yet. Thus, we characterised how pH-related antigen 1 of C. tropicalis (CtPra1) interacts with some of the key complement proteins of the innate immune system. CtPra1 was recombinantly produced using a Kluyveromyces lactis yeast expression system. Recombinant CtPra1, was found to bind human C3 and C3b, central molecules of the complement pathways that are important components of the innate immune system. It was also found to bind human complement regulatory proteins factor-H and C4b-binding protein (C4BP). CtPra1-factor-H and CtPra1-C4BP interactions were found to be ionic in nature as the binding intensity affected by high sodium chloride concentrations. CtPra1 inhibited functional complement activation with different effects on classical (∼20 %), lectin (∼25 %) and alternative (∼30 %) pathways. qPCR experiments using C. tropicalis clinical isolates (oral, blood and peritoneal fluid) revealed relatively higher levels of expression of CtPra1 gene when compared to the reference strain. Native CtPra1 was found to be expressed both as membrane-bound and secretory forms in the clinical isolates. Thus, C. tropicalis appears to be a master of immune evasion by using Pra1 protein. Further investigation using in-vivo models will help ascertain if these proteins can be novel therapeutic targets.
MeSH term(s)	Humans ; Candida tropicalis/immunology ; Complement C3/metabolism ; Complement C3b/metabolism ; Complement C4b-Binding Protein/metabolism ; Hydrogen-Ion Concentration ; Protein Binding ; Fungal Proteins/immunology ; Candidiasis/immunology ; Candidiasis/microbiology
Chemical Substances	Complement C3 ; Complement C3b (80295-43-8) ; Complement C4b-Binding Protein ; PRA1 protein, Candida albicans ; Fungal Proteins
Language	English
Publishing date	2022-11-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	563292-4
ISSN	1878-3279 ; 0171-2985
ISSN (online)	1878-3279
ISSN	0171-2985
DOI	10.1016/j.imbio.2022.152303
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Article ; Online: Structure-function analysis for the development of peptide inhibitors for a Gram-positive quorum sensing system.

Abdullah, Iman Tajer / Ulijasz, Andrew T / Girija, Umakhanth Venkatraman / Tam, Sien / Andrew, Peter / Hiller, Natalia Luisa / Wallis, Russell / Yesilkaya, Hasan

Molecular microbiology

2022 Volume 117, Issue 6, Page(s) 1464–1478

Abstract: The Streptococcus pneumoniae Rgg144/SHP144 regulator-peptide quorum sensing (QS) system is critical for nutrient utilization, oxidative stress response, and virulence. Here, we characterized this system by assessing the importance of each residue within ... ...

Abstract	The Streptococcus pneumoniae Rgg144/SHP144 regulator-peptide quorum sensing (QS) system is critical for nutrient utilization, oxidative stress response, and virulence. Here, we characterized this system by assessing the importance of each residue within the active short hydrophobic peptide (SHP) by alanine-scanning mutagenesis and testing the resulting peptides for receptor binding and activation of the receptor. Interestingly, several of the mutations had little effect on binding to Rgg144 but reduced transcriptional activation appreciably. In particular, a proline substitution (P21A) reduced transcriptional activation by 29-fold but bound with a 3-fold higher affinity than the wild-type SHP. Consistent with the function of Rgg144, the mutant peptide led to decreased utilization of mannose and increased susceptibility to superoxide generator paraquat. Pangenome comparison showed full conservation of P21 across SHP144 allelic variants. Crystallization of Rgg144 in the absence of peptide revealed a comparable structure to the DNA bound and free forms of its homologs suggesting similar mechanisms of activation. Together, these analyses identify key interactions in a critical pneumococcal QS system. Further manipulation of the SHP has the potential to facilitate the development of inhibitors that are functional across strains. The approach described here is likely to be effective across QS systems in multiple species.
MeSH term(s)	Bacterial Proteins/metabolism ; Gene Expression Regulation, Bacterial ; Peptides/metabolism ; Quorum Sensing/genetics ; Streptococcus pneumoniae/metabolism
Chemical Substances	Bacterial Proteins ; Peptides
Language	English
Publishing date	2022-05-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	619315-8
ISSN	1365-2958 ; 0950-382X
ISSN (online)	1365-2958
ISSN	0950-382X
DOI	10.1111/mmi.14921
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Article: Interactions between mannose-binding lectin and MASPs during complement activation by the lectin pathway.

Wallis, Russell

Immunobiology

2006 Volume 212, Issue 4-5, Page(s) 289–299

Abstract: The lectin pathway of complement performs a key role within the immune system by recognising pathogens through patterns of sugar moieties displayed on their cell surfaces and neutralising them via an antibody-independent reaction cascade. While ... ...

Abstract	The lectin pathway of complement performs a key role within the immune system by recognising pathogens through patterns of sugar moieties displayed on their cell surfaces and neutralising them via an antibody-independent reaction cascade. While particularly important during early childhood before the adaptive immune system is established, or when adaptive immunity is compromised, it has a protective function throughout life, neutralising invading pathogens directly and helping to stimulate and direct an effective immune response. Complement activation is initiated when complexes comprising mannose-binding lectin (MBL) or serum ficolins and MBL-associated serine protease-2 (MASP-2) bind to pathogens. Binding induces conformational changes in these complexes, leading to autoactivation of the MASPs, which in turn activate the downstream reaction cascade. A major goal in complement research is to understand the molecular events that trigger complement activation. Over the last few years, structure-function studies have improved our knowledge of the way in which MBL binds to MASPs by defining the portions of these proteins that interact and by solving the structures of key protein fragments. In this review, I will summarise the main findings of these studies and describe current theories to explain how the components combine to initiate the reaction cascade.
MeSH term(s)	Animals ; Complement System Proteins/chemistry ; Complement System Proteins/immunology ; Complement System Proteins/metabolism ; Humans ; Lectins/chemistry ; Lectins/immunology ; Lectins/metabolism ; Mannose/chemistry ; Mannose/immunology ; Mannose/metabolism ; Mannose-Binding Protein-Associated Serine Proteases/chemistry ; Mannose-Binding Protein-Associated Serine Proteases/immunology ; Mannose-Binding Protein-Associated Serine Proteases/metabolism ; Protein Binding ; Signal Transduction/immunology
Chemical Substances	Lectins ; Complement System Proteins (9007-36-7) ; Mannose-Binding Protein-Associated Serine Proteases (EC 3.4.21.-) ; Mannose (PHA4727WTP)
Language	English
Publishing date	2006-12-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	563292-4
ISSN	1878-3279 ; 0171-2985
ISSN (online)	1878-3279
ISSN	0171-2985
DOI	10.1016/j.imbio.2006.11.004
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Article ; Online: Crystal structure of an inulosucrase from Halalkalicoccus jeotgali B3T, a halophilic archaeal strain.

Ghauri, Komal / Pijning, Tjaard / Munawar, Nayla / Ali, Hazrat / Ghauri, Muhammad A / Anwar, Munir A / Wallis, Russell

The FEBS journal

2021 Volume 288, Issue 19, Page(s) 5723–5736

Abstract: Several archaea harbor genes that code for fructosyltransferase (FTF) enzymes. These enzymes have not been characterized yet at structure-function level, but are of extreme interest in view of their potential role in the synthesis of novel compounds for ... ...

Abstract	Several archaea harbor genes that code for fructosyltransferase (FTF) enzymes. These enzymes have not been characterized yet at structure-function level, but are of extreme interest in view of their potential role in the synthesis of novel compounds for food, nutrition, and pharmaceutical applications. In this study, 3D structure of an inulin-type fructan producing enzyme, inulosucrase (InuHj), from the archaeon Halalkalicoccus jeotgali was resolved in its apo form and with bound substrate (sucrose) molecule and first transglycosylation product (1-kestose). This is the first crystal structure of an FTF from halophilic archaea. Its overall five-bladed β-propeller fold is conserved with previously reported FTFs, but also shows some unique features. The InuHj structure is closer to those of Gram-negative bacteria, with exceptions such as residue E266, which is conserved in FTFs of Gram-positive bacteria and has possible role in fructan polymer synthesis in these bacteria as compared to fructooligosaccharide (FOS) production by FTFs of Gram-negative bacteria. Highly negative electrostatic surface potential of InuHj, due to a large amount of acidic residues, likely contributes to its halophilicity. The complex of InuHj with 1-kestose indicates that the residues D287 in the 4B-4C loop, Y330 in 4D-5A, and D361 in the unique α2 helix may interact with longer FOSs and facilitate the binding of longer FOS chains during synthesis. The outcome of this work will provide targets for future structure-function studies of FTF enzymes, particularly those from archaea.
MeSH term(s)	Apoenzymes/chemistry ; Apoenzymes/ultrastructure ; Archaea/enzymology ; Archaea/ultrastructure ; Crystallography, X-Ray ; Halobacteriaceae/enzymology ; Halobacteriaceae/ultrastructure ; Hexosyltransferases/chemistry ; Hexosyltransferases/ultrastructure ; Protein Conformation ; Protein Folding ; Sucrose/chemistry ; Trisaccharides/chemistry
Chemical Substances	Apoenzymes ; Trisaccharides ; 1-kestose (02LN7O412C) ; Sucrose (57-50-1) ; Hexosyltransferases (EC 2.4.1.-) ; inulosucrase (EC 2.4.1.9)
Language	English
Publishing date	2021-04-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15843
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Article ; Online: l-Fucose prevention of renal ischaemia/reperfusion injury in Mice.

Howard, Mark C / Nauser, Christopher L / Farrar, Conrad A / Wallis, Russell / Sacks, Steven H

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2019 Volume 34, Issue 1, Page(s) 822–834

Abstract: In a recent study, we identified a fucosylated damage-associated ligand exposed by ischemia on renal tubule epithelial cells, which after recognition by collectin-11 (CL-11 or collectin kidney 1 (CL-K1)), initiates complement activation and acute kidney ... ...

Abstract	In a recent study, we identified a fucosylated damage-associated ligand exposed by ischemia on renal tubule epithelial cells, which after recognition by collectin-11 (CL-11 or collectin kidney 1 (CL-K1)), initiates complement activation and acute kidney injury. We exploited the ability to increase the local tissue concentration of free l-fucose following systemic administration, in order to block ligand binding by local CL-11 and prevent complement activation. We achieved a thirty-five-fold increase in the intrarenal concentration of l-fucose following an IP bolus given before the ischemia induction procedure - a concentration found to significantly block in vitro binding of CL-11 on hypoxia-stressed renal tubule cells. At this l-fucose dose, complement activation and acute post-ischemic kidney injury are prevented, with additional protection achieved by a second bolus after the induction procedure. CL-11
MeSH term(s)	Acute Kidney Injury/drug therapy ; Acute Kidney Injury/metabolism ; Animals ; Complement Activation/drug effects ; Complement System Proteins/drug effects ; Complement System Proteins/metabolism ; Fucose/metabolism ; Fucose/pharmacokinetics ; Graft Survival/drug effects ; Ischemia/drug therapy ; Ischemia/metabolism ; Kidney/drug effects ; Kidney/metabolism ; Kidney Transplantation/methods ; Mice, Knockout ; Reperfusion Injury/drug therapy ; Reperfusion Injury/metabolism
Chemical Substances	Fucose (28RYY2IV3F) ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2019-11-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.201901582R
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Article: Dominant effects of mutations in the collagenous domain of mannose-binding protein.

Wallis, Russell

Journal of immunology (Baltimore, Md. : 1950)

2002 Volume 168, Issue 9, Page(s) 4553–4558

Abstract: Individuals heterozygous for mutant alleles encoding serum mannose-binding protein (MBP, also known as mannose-binding lectin) show increased susceptibility to infections caused by a wide range of pathogenic microorganisms. To investigate the molecular ... ...

Abstract	Individuals heterozygous for mutant alleles encoding serum mannose-binding protein (MBP, also known as mannose-binding lectin) show increased susceptibility to infections caused by a wide range of pathogenic microorganisms. To investigate the molecular defects associated with heterozygosity, wild-type rat serum MBP polypeptides (MBP-A: 56% identical in sequence to human MBP) and rat MBP polypeptides containing mutations associated with human immunodeficiency have been coexpressed using a well-characterized mammalian expression system. The resulting proteins are secreted almost exclusively as heterooligomers that are defective in activating the complement cascade. Functional defects are caused by structural changes to the N-terminal collagenous and cysteine-rich domains of MBP, disrupting interactions with associated serine proteases. The dominant effects of the mutations demonstrate how the presence of a single mutant allele gives rise to the molecular defects that lead to the disease phenotype in heterozygous individuals.
MeSH term(s)	Animals ; Binding, Competitive ; Carrier Proteins/chemistry ; Carrier Proteins/genetics ; Carrier Proteins/physiology ; Collagen/chemistry ; Collectins ; Complement Fixation Tests ; Mannose-Binding Protein-Associated Serine Proteases ; Mutation ; Protein Structure, Tertiary ; Rats ; Serine Endopeptidases/metabolism
Chemical Substances	Carrier Proteins ; Collectins ; Collagen (9007-34-5) ; Mannose-Binding Protein-Associated Serine Proteases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2002-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.168.9.4553
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Article: Structural and functional aspects of complement activation by mannose-binding protein.

Wallis, Russell

Immunobiology

2002 Volume 205, Issue 4-5, Page(s) 433–445

Abstract: Serum mannose-binding protein (MBP) is the first component of the lectin pathway of the complement cascade. It binds to sugars on the surface of pathogenic microorganisms and triggers complement fixation by activating an associated serine protease, ... ...

Abstract	Serum mannose-binding protein (MBP) is the first component of the lectin pathway of the complement cascade. It binds to sugars on the surface of pathogenic microorganisms and triggers complement fixation by activating an associated serine protease, designated MBP-associated serine protease-2 (MASP-2). Recent studies have provided insight into the interactions between MBP and MASP-2 that trigger complement activation. MBP/MASP complexes share many features with the C1 complex of the classical pathway. The relatively simple MBP/MASP complexes serve as useful models for understanding activation of the classical pathway of the complement cascade.
MeSH term(s)	Animals ; Complement Activation/physiology ; Complement Pathway, Classical/physiology ; Complement Pathway, Mannose-Binding Lectin/physiology ; Humans ; Mannose-Binding Lectin/chemistry ; Mannose-Binding Lectin/metabolism ; Mannose-Binding Protein-Associated Serine Proteases ; Serine Endopeptidases/metabolism ; Structure-Activity Relationship
Chemical Substances	Mannose-Binding Lectin ; Mannose-Binding Protein-Associated Serine Proteases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2002-09
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	563292-4
ISSN	1878-3279 ; 0171-2985
ISSN (online)	1878-3279
ISSN	0171-2985
DOI	10.1078/0171-2985-00144
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Article ; Online: Inactivation of the Complement Lectin Pathway by Candida tropicalis Secreted Aspartyl Protease-1.

Valand, Nisha / Brunt, Emily / Gazioglu, Ozcan / Yesilkaya, Hasan / Mitchell, Daniel / Horley, Neill / Arroo, Randolph / Kishore, Uday / Wallis, Russell / Venkatraman Girija, Umakhanth

Immunobiology

2022 Volume 227, Issue 6, Page(s) 152263

Abstract: Candida tropicalisis an opportunistic fungal pathogen and is one of the most frequently isolated non-albicans species. It can cause localised as well as invasive systemic infections particularly in immunocompromised patients. Increased resistance to ... ...

Abstract	Candida tropicalisis an opportunistic fungal pathogen and is one of the most frequently isolated non-albicans species. It can cause localised as well as invasive systemic infections particularly in immunocompromised patients. Increased resistance to common anti-fungal drugs is an emerging problem. In order to establish disseminated infections, Candida has evolved several strategies to escape the host immune system. A detailed understanding of how C. tropicalis escapes the host immune attack is needed as it can help develop novel anti-fungal therapies. Secreted aspartyl proteinases (Saps) of C. albicans have been shown to be determinants of virulence and immune evasion. However, the immune evasion properties of C. tropicalis Saps have been poorly characterised. This study investigated the immune evasion properties of C. tropicalis secreted aspartic protease 1 (Sapt1).Sapt1 was recombinantly produced using a Kluyveromyces lactis yeast expression system. A range of complement proteins and immunogloublins were screened to test if Sapt1 had any proteolytic activity. Sapt1 efficiently cleaved human mannose-binding lectin (MBL) and collectin-11, which are the initiating molecules of the lectin pathway of the complement system, but not l-ficolin. In addition, Sapt1 cleaved DC-SIGN, the receptor on antigen presenting dendritic cells. Proteolysis was prominent in acidic condition (pH 5.2), a characteristic of aspartyl protease. No proteolytic activity was detected against complement proteins C1q, C3, C3b, IgG and IgA. In view of the ability of Sapt1 to cleave MBL and collectin-11, we found that Sapt1 could prevent activation of the complement lectin pathway. RT-qPCR analysis using three different C. tropicalis clinical isolates (oral, blood and peritoneal dialysis fluid) revealed relatively higher levels of mRNA expression of Sapt1 gene when compared to a reference strain; Sapt1 protein was found to be secreted by all the tested strains. Lectin pathway and its initiating components are crucial to provide front line defence against Candida infections. For the first time, we have shown that a Candida protease can proteolytically degrade the key initiating components of lectin pathway and inhibit complement activation. Findings from this study highlight the importance of exploring Sapt1 as a potential therapeutic target. We conclude that C. tropicalis secretes Sapt1 to target the complement lectin pathway, a key pattern recognition and clearance mechanism, for its survival and pathogenesis.
MeSH term(s)	Humans ; Candida tropicalis/metabolism ; Complement Pathway, Mannose-Binding Lectin ; Mannose-Binding Lectin/metabolism ; Candida albicans/physiology ; Candida ; Aspartic Acid Proteases/genetics ; Aspartic Acid Proteases/metabolism ; Lectins/metabolism ; Complement System Proteins/metabolism
Chemical Substances	Mannose-Binding Lectin ; Aspartic Acid Proteases (EC 3.4.-) ; Lectins ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2022-08-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	563292-4
ISSN	1878-3279 ; 0171-2985
ISSN (online)	1878-3279
ISSN	0171-2985
DOI	10.1016/j.imbio.2022.152263
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Article ; Online: Formation of pre-pore complexes of pneumolysin is accompanied by a decrease in short-range order of lipid molecules throughout vesicle bilayers.

Faraj, Bayan H A / Collard, Liam / Cliffe, Rachel / Blount, Leanne A / Lonnen, Rana / Wallis, Russell / Andrew, Peter W / Hudson, Andrew J

Scientific reports

2020 Volume 10, Issue 1, Page(s) 4585

Abstract: Oligomers of pneumolysin form transmembrane channels in cholesterol-containing lipid bilayers. The mechanism of pore formation involves a multistage process in which the protein, at first, assembles into a ring-shaped complex on the outer-bilayer leaflet. ...

Abstract	Oligomers of pneumolysin form transmembrane channels in cholesterol-containing lipid bilayers. The mechanism of pore formation involves a multistage process in which the protein, at first, assembles into a ring-shaped complex on the outer-bilayer leaflet. In a subsequent step, the complex inserts into the membrane. Contrary to most investigations of pore formation that have focussed on protein changes, we have deduced how the lipid-packing order is altered in different stages of the pore-forming mechanism. An optical tweezing apparatus was used, in combination with microfluidics, to isolate large-unilamellar vesicles and control exposure of the bilayer to pneumolysin. By monitoring Raman-scattered light from a single-trapped liposome, the effect of the protein on short-range order and rotational diffusion of lipids could be inferred from changes in the envelope of the C-H stretch. A significant change in the lipid-packing order takes place during assembly of pre-pore oligomers. We were not able to detect a change in the lipid-packing order during the initial stage of protein binding, or any further change during the insertion of oligomers. Pre-pore complexes induce a transformation in which a bilayer, resembling a liquid-ordered phase is changed into a bilayer resembling a fluid-liquid-disordered phase surrounding ordered microdomains enriched in cholesterol and protein complexes.
MeSH term(s)	Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Cholesterol/chemistry ; Cholesterol/metabolism ; Hemolysis ; Lipid Bilayers/chemistry ; Lipid Bilayers/metabolism ; Microfluidic Analytical Techniques ; Models, Molecular ; Mutation ; Optical Tweezers ; Protein Binding ; Spectrum Analysis, Raman ; Streptococcus pneumoniae/metabolism ; Streptolysins/chemistry ; Streptolysins/genetics ; Streptolysins/metabolism ; Unilamellar Liposomes/chemistry ; Unilamellar Liposomes/metabolism
Chemical Substances	Bacterial Proteins ; Lipid Bilayers ; Streptolysins ; Unilamellar Liposomes ; plY protein, Streptococcus pneumoniae ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2020-03-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-60348-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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