scholarly journals The leader peptide of mutacin 1140 has distinct structural components compared to related class I lantibiotics

2014 ◽  
Vol 3 (6) ◽  
pp. 961-972 ◽  
Author(s):  
Jerome Escano ◽  
Byron Stauffer ◽  
Jacob Brennan ◽  
Monica Bullock ◽  
Leif Smith
Keyword(s):  
Class I ◽  
Leader Peptide ◽  
Structural Components ◽  
Mutacin 1140

scholarly journals TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide

1998 ◽  
Vol 8 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Veronique M. Braud ◽  
David S.J. Allan ◽  
Douglas Wilson ◽  
Andrew J. McMichael
Keyword(s):  
Mhc Class I ◽  
Surface Expression ◽  
Class I ◽  
Leader Peptide

scholarly journals Strictly transporter of antigen presentation (TAP)-dependent presentation of an immunodominant cytotoxic T lymphocyte epitope in the signal sequence of a virus protein.

1995 ◽  
Vol 182 (5) ◽  
pp. 1615-1619 ◽  
Author(s):  
J Hombach ◽  
H Pircher ◽  
S Tonegawa ◽  
R M Zinkernagel
Keyword(s):  
Antigen Presentation ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Signal Sequence ◽  
Class I ◽  
Signal Peptidase ◽  
Leader Peptide ◽  
Virus Protein ◽  
Mhc Class I Molecules

Peptides presented by major histocompatibility complex (MHC) class I molecules are derived from intracellularly synthesized proteins. Cytosolic proteins are fragmented into peptides, which are subsequently transported via the transporter of antigen presentation (TAP) into the endoplasmic reticulum (ER), where they bind to MHC class I molecules. We have investigated the requirements for MHC class I presentation of the immunodominant gp33 cytotoxic T lymphocyte epitope of the lymphocytic choriomeningitis virus. This epitope is located within the leader peptide of the virus glycoprotein. Such an epitope is expected to be presented in a TAP-independent manner, since it is released into the ER by signal peptidase. Taking advantage of TAP1-/- mice, however, we show both in vitro and in vivo that, after virus infection, the presentation of the gp33 epitope is strictly dependent on a functional TAP heterodimer. The results are discussed with respect to peptide trimming processes in the ER.

scholarly journals Biosynthesis and Transport of the Lantibiotic Mutacin 1140 Produced by Streptococcus mutans

2015 ◽  
Vol 197 (7) ◽  
pp. 1173-1184 ◽  
Author(s):  
Jerome Escano ◽  
Byron Stauffer ◽  
Jacob Brennan ◽  
Monica Bullock ◽  
Leif Smith
Keyword(s):  
Streptococcus Mutans ◽  
Posttranslational Modifications ◽  
Cleavage Site ◽  
Peptide Sequence ◽  
Leader Peptide ◽  
Peptide Antibiotics ◽  
The Core ◽  
Core Peptide ◽  
Mutacin 1140 ◽  
Secondary Cleavage

ABSTRACTLantibiotics are ribosomally synthesized peptide antibiotics composed of an N-terminal leader peptide that is cleaved to yield the active antibacterial peptide. Significant advancements in molecular tools that promote the study of lantibiotic biosynthesis can be used inStreptococcus mutans. Herein, we further our understanding of leader peptide sequence and core peptide structural requirements for the biosynthesis and transport of the lantibiotic mutacin 1140. Our study on mutacin 1140 biosynthesis shows a dedicated secondary cleavage site within the leader peptide and the dependency of transport on core peptide posttranslational modifications (PTMs). The secondary cleavage site on the leader peptide is found at the −9 position, and secondary cleavage occurs before the core peptide is transported out of the cell. The coordinated cleavage at the −9 position was absent in alanTdeletion strain, suggesting that the core peptide interaction with the LanT transporter enables uniform cleavage at the −9 position. Following transport, the LanP protease was found to be tolerant to a wide variety of amino acid substitutions at the primary leader peptide cleavage site, with the exception of arginine at the −1 position. Several leader and core peptide mutations produced core peptide variants that had intermediate stages of PTM enzyme modifications, supporting the concept that PTM enzyme modifications, secondary cleavage, and transport are occurring in a highly coordinated fashion.IMPORTANCEMutacin 1140 belongs to the class I lantibiotic family of ribosomally synthesized and posttranslationally modified peptides (RiPPs). The biosynthesis of mutacin 1140 is a highly efficient process which does not lead to a discernible level of production of partially modified core peptide variants. The products isolated from an extensive mutagenesis study on the leader and core peptides of mutacin 1140 show that the posttranslational modifications (PTMs) on the core peptide occur under a highly coordinated dynamic process. PTMs are dictated by the distance of the core peptide modifiable residues from PTM enzyme active sites. The formation of lanthionine rings aids in the formation of successive PTMs, as was observed in a peptide variant lacking a C-terminal decarboxylation.

scholarly journals H2-M3 Restricted Presentation of a Listeria-derived Leader Peptide

1998 ◽  
Vol 187 (10) ◽  
pp. 1711-1719 ◽  
Author(s):  
Michael F. Princiotta ◽  
Laurel L. Lenz ◽  
Michael J. Bevan ◽  
Uwe D. Staerz
Keyword(s):  
Host Cell ◽  
Antigen Processing ◽  
Class I ◽  
Leader Peptide ◽  
Mhc Class Ib ◽  
Expression Library ◽  
Genomic Expression ◽  
Bacterial Proteins ◽  
Cell Class ◽  
Formyl Peptide

Protective immunity to infection by many intracellular pathogens requires recognition by cytotoxic T lymphocytes (CTLs) of antigens presented on major histocompatibility complex (MHC) class I molecules. To be presented for recognition by pathogen-specific CTLs, these antigens must gain access to the host cell class I processing pathway. In the case of intracellular bacterial pathogens, the majority of bacterial proteins are retained within the bacterial membrane and therefore remain inaccessible to the host cell for antigen processing. We have isolated a CTL clone from a C57BL/6 mouse infected with the intracellular gram-positive bacterium Listeria monocytogenes (LM) and have identified the source of the antigen. Using a genomic expression library, we determined that the clone recognizes an antigenic N-formyl peptide presented by the nonpolymorphic murine MHC class Ib molecule, H2-M3. Several lengths of this peptide were able to sensitize cells for lysis by this CTL clone. The source of this antigenic peptide is a 23–amino acid polypeptide encoded at the start of a polycistronic region. Analysis of mRNA secondary structure of this region suggests that this polypeptide may be a leader peptide encoded by a transcriptional attenuator.

scholarly journals Recipient HLA-B Leader Genotype, and Its Relationship to Total KIR Missing Ligand, Informs Relapse and Survival Following Haploidentical Transplantation Using Post-Transplant Cyclophosphamide

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 418-418
Author(s):  
Scott R. Solomon ◽  
Michael T Aubrey ◽  
Xu Zhang ◽  
Katelin C Jackson ◽  
Christina L Roark ◽  
...  
Keyword(s):  
Nk Cells ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Killer Cell ◽  
Class I ◽  
Leader Peptide ◽  
Negative Consequences ◽  
Post Transplant ◽  
Leader Peptides

Abstract In addition to donor T cells, natural killer (NK) cells are proposed to play a significant role in the graft-versus-leukemia (GVL) effect following haploidentical donor transplantation (HIDT). Following HIDT, donor NK cells express activating (NKG2C) receptors (Ciurea, Leukemia 2021), whose ligand is the non-classical human leukocyte antigen, HLA-E. For surface expression, HLA-E requires binding of leader peptides derived from class I HLA molecules. The rs1050458C/T dimorphism at position -21 of exon 1 of HLA-B gives rise to leader peptides with either methionine (M) or threonine (T) at the second residue of the processed leader peptide. M-containing HLA-B leader peptides promote higher HLA-E expression than T-leaders, potentially favoring more robust natural NK cell recognition of HLA-E-expressing tumor cells. Alternatively, donor NK cells can be activated through inhibitory killer cell immunoglobulin-like receptors (iKIR: 2DL1, 2DL23, 3DL1, 3DL2), if they fail to engage a corresponding class I HLA ligand on recipient leukemia cells (missing ligand (ML) paradigm). We hypothesized that M-containing B-leaders (either MM or MT genotype), and potentially its association with KIR ML, may inform relapse and survival after HIDT using post-transplant cyclophosphamide (PTCy). A total of 322 patients with acute leukemia, MDS, lymphoma, CLL or CML, receiving a HIDT-PTCy from a single institution were evaluated with a median follow-up time of 45 months [range 6, 184]. Baseline characteristics included a median age of 50 years [19, 80], 47% non-white, HCT-CI ≥3 in 50%, PBSC graft in 80%, and myeloablative conditioning in 49%. M-containing B-leader genotype (either MM or MT) was seen in 42% and 44% of recipients and donors, respectively. The B-leader on the unshared donor-recipient haplotypes was matched (either T or M) in 61% of transplants. ML for iKIR 2DL1, 2DL23, 3DL1, and 3DL2 was noted in 29%, 20%, 24% and 72% respectively. Total ML was 0, 1, 2 and 3 in 10%, 43%, 40% and 7% respectively. In univariate analysis, an M-containing recipient B-leader genotype [R(M+)] improved OS and DFS compared to a recipient TT genotype [R(M-)] (75 vs. 53%, p<0.001; 66 vs. 47%, p<0.001), which was primarily due to a lower risk of relapse/progression (24% vs. 38%, p=0.012). In regard to total iKIR ML, the presence of 2-3 ML was associated with better overall (OS) and disease-free (DFS) survival compared with 0-1 (67% vs. 57%, p=0.08; 62% vs. 48%, p=0.019), which was due to lower relapse/progression (25% vs. 38%, p=0.015). There was no association of either recipient B-leader or total iKIR ML with the incidence of NRM, acute or chronic GVHD. When recipient B-leader and ML were combined, the detrimental effect of a R(M-) genotype was seen exclusively in patients with ML 0-1 (see figure). DFS for R(M-)/ML(0-1), R(M+)/ML(0-1), R(M-)/ML(2-3), R(M+)/ML(2-3) was 36%, 68%, 65% and 60%, respectively (p<0.001). Corresponding relapse/progression rates were 49%, 22%, 26% and 25%, respectively (P<0.001). In multivariate analysis, controlling for patient age/sex/race, disease risk index, donor age, HLA-DR mm, HLA-DP npmm and year of transplantation, both recipient B leader and total iKIR ML were independently associated with DFS (HR 0.57, p=0.002 and HR 0.67, p=0.026) and relapse/progression (HR 0.55, p=0.006 and HR 0.55, p=0.007). In summary, a recipient M-containing B-leader genotype (MM or MT) reduces relapse and improves survival following HIDT-PTCy, presumably through HLA-E-mediated effector cell engagement. Furthermore, the negative consequences of low total ML for iKIR, in terms of increased relapse risk and lower DFS, can be mitigated when a R(M+) B-leader is present. In addition to the clinical importance of this novel finding for optimizing HIDT-PTCy, it further supports the role of alloreactive donor NK cells for optimal GVL in this context. Figure 1 Figure 1. Disclosures Solh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; BMS: Consultancy.

Association of high HLA-E expression during acute cellular rejection and numbers of HLA class I leader peptide mismatches with reduced renal allograft survival

Immunobiology ◽  
2017 ◽  
Vol 222 (3) ◽  
pp. 536-543 ◽  
Author(s):  
Hana Guberina ◽  
Vera Rebmann ◽  
Bettina Wagner ◽  
Fabiola da Silva Nardi ◽  
Phillip Dziallas ◽  
...  
Keyword(s):  
Renal Allograft ◽  
Hla Class I ◽  
Acute Cellular Rejection ◽  
Class I ◽  
Leader Peptide ◽  
Allograft Survival ◽  
Cellular Rejection

scholarly journals Production of a Class II Two-Component Lantibiotic of Streptococcus pneumoniae Using the Class I Nisin Synthetic Machinery and Leader Sequence

2010 ◽  
Vol 54 (4) ◽  
pp. 1498-1505 ◽  
Author(s):  
Joanna A. Majchrzykiewicz ◽  
Jacek Lubelski ◽  
Gert N. Moll ◽  
Anneke Kuipers ◽  
Jetta J. E. Bijlsma ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Class Ii ◽  
Leader Sequence ◽  
Biologically Active ◽  
Class I ◽  
Leader Peptide ◽  
Small Peptides ◽  
Nisin Production ◽  
Two Component

ABSTRACT Recent studies showed that the nisin modification machinery can successfully dehydrate serines and threonines and introduce lanthionine rings in small peptides that are fused to the nisin leader sequence. This opens up exciting possibilities to produce and engineer larger antimicrobial peptides in vivo. Here we demonstrate the exploitation of the class I nisin production machinery to generate, modify, and secrete biologically active, previously not-yet-isolated and -characterized class II two-component lantibiotics that have no sequence homology to nisin. The nisin synthesis machinery, composed of the modification enzymes NisB and NisC and the transporter NisT, was used to modify and secrete a putative two-component lantibiotic of Streptococcus pneumoniae. This was achieved by genetically fusing the propeptide-encoding sequences of the spr1765 (pneA1) and spr1766 (pneA2) genes to the nisin leader-encoding sequence. The chimeric prepeptides were secreted out of Lactococcus lactis, purified by cation exchange fast protein liquid chromatography, and further characterized. Mass spectrometry analyses demonstrated the presence and partial localization of multiple dehydrated serines and/or threonines and (methyl)lanthionines in both peptides. Moreover, after cleavage of the leader peptide from the prepeptides, both modified propeptides displayed antimicrobial activity against Micrococcus flavus. These results demonstrate that the nisin synthetase machinery can be successfully used to modify and produce otherwise difficult to obtain antimicrobially active lantibiotics.

Electron probe x-ray microanalysis and electron microscopy of amino acid absorption and transport by the small intestine: inhibition by chemical poisons and correlation to the elemental composition of the epithelial cells

1986 ◽  
Vol 44 ◽  
pp. 134-135
Author(s):  
A. J. Tousimis
Keyword(s):  
Small Intestine ◽  
Amino Acid ◽  
Epithelial Cells ◽  
Elemental Composition ◽  
Isotope Labeling ◽  
Structural Components ◽  
X Ray ◽  
Human Small Intestine ◽  
Transport Studies

The elemental composition of amino acids is similar to that of the major structural components of the epithelial cells of the small intestine and other tissues. Therefore, their subcellular localization and concentration measurements are not possible by x-ray microanalysis. Radioactive isotope labeling: I131-tyrosine, Se75-methionine and S35-methionine have been successfully employed in numerous absorption and transport studies. The latter two have been utilized both in vitro and vivo, with similar results in the hamster and human small intestine. Non-radioactive Selenomethionine, since its absorption/transport behavior is assumed to be the same as that of Se75- methionine and S75-methionine could serve as a compound tracer for this amino acid.

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