Structure of Csd3 fromHelicobacter pylori, a cell shape-determining metallopeptidase

Helicobacter pyloriis associated with various gastrointestinal diseases such as gastritis, ulcers and gastric cancer. Its colonization of the human gastric mucosa requires high motility, which depends on its helical cell shape. Seven cell shape-determining genes (csd1,csd2,csd3/hdpA,ccmA,csd4,csd5andcsd6) have been identified inH. pylori. Their proteins play key roles in determining the cell shape through modifications of the cell-wall peptidoglycan by the alteration of cross-linking or by the trimming of peptidoglycan muropeptides. Among them, Csd3 (also known as HdpA) is a bifunctional enzyme. Its D,D-endopeptidase activity cleaves the D-Ala4-mDAP3peptide bond between cross-linked muramyl tetrapeptides and pentapeptides. It is also a D,D-carboxypeptidase that cleaves off the terminal D-Ala5from the muramyl pentapeptide. Here, the crystal structure of this protein has been determined, revealing the organization of its three domains in a latent and inactive state. The N-terminal domain 1 and the core of domain 2 share the same fold despite a very low level of sequence identity, and their surface-charge distributions are different. The C-terminal LytM domain contains the catalytic site with a Zn2+ion, like the similar domains of other M23 metallopeptidases. Domain 1 occludes the active site of the LytM domain. The core of domain 2 is held against the LytM domain by the C-terminal tail region that protrudes from the LytM domain.

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Structural basis for the peptidoglycan recognition by Helicobacter pylori Csd4

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314091827 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C817-C817

Author(s):

Hyoun Sook Kim ◽

Byung Woo Han ◽

Byung Il Lee ◽

Se Won Suh

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Cell Shape ◽

Gastrointestinal Diseases ◽

Structural Basis ◽

Free Form ◽

Peptic Ulcers ◽

Carboxypeptidase H ◽

Ligand Free ◽

H Pylori

Helicobacter pylori infection causes a variety of gastrointestinal diseases including peptic ulcers and gastric cancer. The colonization of this bacterium in the gastric mucosa is required for the survival in the stomach. Its colonization of the gastric mucosa of human stomach depends on its motility, which is facilitated by the helical cell shape. In H. pylori, crosslinking relaxation or trimming of peptidoglycan muropeptide affects the helical shape. Among several cell shape-determining peptidoglycan hydrolases identified in H. pylori, Csd4 is a Zn2+-dependent D,L-carboxypeptidase that cleaves the bond between the γ-D-Glu and mDAP bond of the uncrosslinked tripeptide of peptidoglycan (L-Ala-γ-D-Glu-mDAP) to produce L-Ala-γ-D-Glu dipeptide and mDAP, promoting the helical cell shape. Inhibition of D,L-carboxypeptidase activity of Csd4 may represent a novel therapeutic approach. We report here the crystal structures of H. pylori Csd4 in three different states: the ligand-free form, the substrate-bound form, and the product-bound form. H. pylori Csd4 consists of three domains: an N-terminal D,L-carboxypeptidase domain, a novel β-barrel domain, and a C-terminal immunoglobulin-like domain. Our ligand-bound structures provide structural basis of peptidoglycan recognition by D,L-carboxypeptidase. H. pylori Csd4 recognizes primarily the terminal mDAP of the tripeptide substrate and undergoes a significant structural change upon binding either mDAP or mDAP-containing tripeptide.

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Structural basis for the recognition of muramyltripeptide byHelicobacter pyloriCsd4, aD,L-carboxypeptidase controlling the helical cell shape

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s1399004714018732 ◽

2014 ◽

Vol 70 (11) ◽

pp. 2800-2812 ◽

Cited By ~ 14

Author(s):

Hyoun Sook Kim ◽

Jieun Kim ◽

Ha Na Im ◽

Doo Ri An ◽

Mijoon Lee ◽

...

Keyword(s):

Crystal Structure ◽

Cell Shape ◽

Gastrointestinal Diseases ◽

Human Stomach ◽

Structural Basis ◽

Cross Linking ◽

Peptic Ulcers ◽

Significant Structural Change ◽

Peptidoglycan Hydrolases ◽

H Pylori

Helicobacter pyloriinfection causes a variety of gastrointestinal diseases, including peptic ulcers and gastric cancer. Its colonization of the gastric mucosa of the human stomach is a prerequisite for survival in the stomach. Colonization depends on its motility, which is facilitated by the helical shape of the bacterium. InH. pylori, cross-linking relaxation or trimming of peptidoglycan muropeptides affects the helical cell shape. Csd4 has been identified as one of the cell shape-determining peptidoglycan hydrolases inH. pylori. It is a Zn2+-dependent D,L-carboxypeptidase that cleaves the bond between the γ-D-Glu and themDAP of the non-cross-linked muramyltripeptide (muramyl-L-Ala-γ-D-Glu-mDAP) of the peptidoglycan to produce the muramyldipeptide (muramyl-L-Ala-γ-D-Glu) andmDAP. Here, the crystal structure ofH. pyloriCsd4 (HP1075 in strain 26695) is reported in three different states: the ligand-unbound form, the substrate-bound form and the product-bound form.H. pyloriCsd4 consists of three domains: an N-terminal D,L-carboxypeptidase domain with a typical carboxypeptidase fold, a central β-barrel domain with a novel fold and a C-terminal immunoglobulin-like domain. The D,L-carboxypeptidase domain recognizes the substrate by interacting primarily with the terminalmDAP moiety of the muramyltripeptide. It undergoes a significant structural change upon binding eithermDAP or themDAP-containing muramyltripeptide. It it also shown that Csd5, another cell-shape determinant inH. pylori, is capable of interacting not only withH. pyloriCsd4 but also with the dipeptide product of the reaction catalyzed by Csd4.

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H. pylori down-regulates TRAIL (DR4)-receptors in the human gastric mucosa, a possible mechanism for chronic persistence

Gastroenterology ◽

10.1016/s0016-5085(01)80401-7 ◽

2001 ◽

Vol 120 (5) ◽

pp. A81-A81

Author(s):

B NEU ◽

R RAD ◽

M NEUHOFER ◽

C TRAUTWEIN ◽

M GERHARD ◽

...

Keyword(s):

Gastric Mucosa ◽

Human Gastric Mucosa ◽

H Pylori

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The correlation between lncRNAs and Helicobacter pylori in gastric cancer

Pathogens and Disease ◽

10.1093/femspd/ftaa004 ◽

2019 ◽

Vol 77 (9) ◽

Author(s):

Narges Dastmalchi ◽

Seyed Mahdi Banan Khojasteh ◽

Mirsaed Miri Nargesi ◽

Reza Safaralizadeh

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Molecular Mechanisms ◽

Gastrointestinal Diseases ◽

Mechanisms Of Action ◽

Molecular Pathways ◽

Gastric Diseases ◽

Non Coding Rnas ◽

H Pylori ◽

The Relationship

ABSTRACT Helicobacter pylori infection performs a key role in gastric tumorigenesis. Long non-coding RNAs (lncRNAs) have demonstrated a great potential to be regarded as effective malignancy biomarkers for various gastrointestinal diseases including gastric cancer (GC). The present review highlights the relationship between lncRNAs and H. pylori in GC. Several studies have examined not only the involvement of lncRNAs in H. pylori-associated GC progression but also their molecular mechanisms of action. Among the pertinent studies, some have addressed the effects of H. pylori infection on modulatory networks of lncRNAs, while others have evaluated the effects of changes in the expression level of lncRNAs in H. pylori-associated gastric diseases, especially GC. The relationship between lncRNAs and H. pylori was found to be modulated by various molecular pathways.

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Disome-seq reveals widespread ribosome collisions that promote cotranslational protein folding

Genome Biology ◽

10.1186/s13059-020-02256-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Taolan Zhao ◽

Yan-Ming Chen ◽

Yu Li ◽

Jia Wang ◽

Siyu Chen ◽

...

Keyword(s):

Protein Quality ◽

Peptide Bond ◽

Peptide Bond Formation ◽

Translation Elongation ◽

Cryo Electron Microscopy ◽

Cotranslational Folding ◽

A Cell ◽

Exit Tunnel ◽

Hidden Layer ◽

A Site

Abstract Background The folding of proteins is challenging in the highly crowded and sticky environment of a cell. Regulation of translation elongation may play a crucial role in ensuring the correct folding of proteins. Much of our knowledge regarding translation elongation comes from the sequencing of mRNA fragments protected by single ribosomes by ribo-seq. However, larger protected mRNA fragments have been observed, suggesting the existence of an alternative and previously hidden layer of regulation. Results In this study, we performed disome-seq to sequence mRNA fragments protected by two stacked ribosomes, a product of translational pauses during which the 5′-elongating ribosome collides with the 3′-paused one. We detected widespread ribosome collisions that are related to slow ribosome release when stop codons are at the A-site, slow peptide bond formation from proline, glycine, asparagine, and cysteine when they are at the P-site, and slow leaving of polylysine from the exit tunnel of ribosomes. The structure of disomes obtained by cryo-electron microscopy suggests a different conformation from the substrate of the ribosome-associated protein quality control pathway. Collisions occurred more frequently in the gap regions between α-helices, where a translational pause can prevent the folding interference from the downstream peptides. Paused or collided ribosomes are associated with specific chaperones, which can aid in the cotranslational folding of the nascent peptides. Conclusions Therefore, cells use regulated ribosome collisions to ensure protein homeostasis.

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H. pylori cagA, vacA and iceA genotype associations with gastroesophageal reflux disease (GERD) compared to other upper gastrointestinal diseases

Gastroenterology ◽

10.1016/s0016-5085(00)80910-5 ◽

2000 ◽

Vol 118 (4) ◽

pp. A1266

Author(s):

Andreas Leodolter ◽

Kathlen Wolle ◽

Matthias Ebert ◽

Wolfgang Koenig ◽

Peter Malfertheiner

Keyword(s):

Gastroesophageal Reflux Disease ◽

Gastroesophageal Reflux ◽

Reflux Disease ◽

Gastrointestinal Diseases ◽

H Pylori ◽

Upper Gastrointestinal

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Vonoprozan: potentially new first-line treatment for delayed upper gastrointestinal bleeds following endoscopic procedures? A letter to the editor

Journal of the Pakistan Medical Association ◽

10.47391/jpma.4136 ◽

2022 ◽

Vol 71 (12) ◽

pp. 2838-2838

Author(s):

Muhammad Umer ◽

Syed Wasif Bukhari

Keyword(s):

Endoscopic Submucosal Dissection ◽

Gastrointestinal Diseases ◽

High Dose ◽

First Line ◽

Gastroesophageal Varices ◽

Delayed Bleeding ◽

Submucosal Dissection ◽

Significant Difference ◽

H Pylori ◽

Line Of Therapy

Endoscopy nowadays is widely used as a diagnostic and therapeutic tool for various gastrointestinal diseases due to it being less invasive and safer. However, amongst some adverse events is delayed bleeding. The definition of delayed bleeding requires endoscopic hemostasis and/or blood transfusion after at least two days of treatment. (1) Oesophageal cancer is comparatively more common in Pakistan, being 7th most common malignancy in men and 6th most common in women in Karachi. (2) Oesophageal endoscopic submucosal dissection (E-ESD) employed in the treatment of the above- mentioned cancer has an incidence of delayed bleeding of about 1.3-6.7%. (1) The prevalence of gastric cancer across Pakistan was about 2-18% (3), for which endoscopic submucosal dissection is often used has an incidence of delayed bleeding of 4.7-15.6%. (1) Endoscopic therapy for gastroesophageal varices can also result in delayed bleeding, the incidence of which easily reaches up to 10%. (1) In a retrospective cohort study of 124,422 patients conducted in Japan, it was found that vonoprazan was more effective in reducing the risk of delayed bleeding compared to omeprazole. (OR= 0.75) (1) Vonoprazan works by competitively inhibiting the potassium-acid channel resulting in strong and sustained acid inhibition. (4) It was also found to have a superior effect in the eradication of H Pylori and an equal effect in acid-related disorders. (5) In the retrospective study mentioned above, it is also worth noting that the efficacy of vonoprazan was variable with respect to procedures and was most prominent with gastroduodenal endoscopic submucosal dissection (OR=0.70). (1) Other procedures did not elicit any significant difference. In addition, standard/high dose vonoprazan proved to be most efficacious in reducing the risk of delayed bleeding compared with standard/high-dose PPI and low-dose vonoprazan. It was also observed that patients taking anti-thrombotic medications at a higher risk of delayed bleeding also benefited from high-dose vonoprazan. (OR=0.74) (1) The findings above compel the conclusion that high dose vonoprazan should be ideal for reducing the risk of delayed bleeding in patients who have undergone gastroduodenal endoscopic submucosal dissection and/or are on anti-thrombotics. Though high-dose vonoprazan does look promising, it is imperative that more randomized controlled trials on more diverse populations be conducted to further explore its efficacy and safety as the drug might be a potential first line of therapy.

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Form follows function: how muscle shape is regulated by work

Journal of Applied Physiology ◽

10.1152/jappl.2000.88.3.1127 ◽

2000 ◽

Vol 88 (3) ◽

pp. 1127-1132 ◽

Cited By ~ 87

Author(s):

Brenda Russell ◽

Delara Motlagh ◽

William W. Ashley

Keyword(s):

Muscle Cell ◽

Cell Shape ◽

Force Production ◽

Cardiac Cells ◽

Cross Sectional Area ◽

Dynamic Responses ◽

Mechanical Activity ◽

Sectional Area ◽

Cross Sectional ◽

A Cell

What determines the shape, size, and force output of cardiac and skeletal muscle? Chicago architect Louis Sullivan (1856–1924), father of the skyscraper, observed that “form follows function.” This is as true for the structural elements of a striated muscle cell as it is for the architectural features of a building. Function is a critical evolutionary determinant, not form. To survive, the animal has evolved muscles with the capacity for dynamic responses to altered functional demand. For example, work against an increased load leads to increased mass and cross-sectional area (hypertrophy), which is directly proportional to an increased potential for force production. Thus a cell has the capacity to alter its shape as well as its volume in response to a need for altered force production. Muscle function relies primarily on an organized assembly of contractile and other sarcomeric proteins. From analysis of homogenized cells and molecular and biochemical assays, we have learned about transcription, translation, and posttranslational processes that underlie protein synthesis but still have done little in addressing the important questions of shape or regional cell growth. Skeletal muscles only grow in length as the bones grow; therefore, most studies of adult hypertrophy really only involve increased cross-sectional area. The heart chamber, however, can extend in both longitudinal and transverse directions, and cardiac cells can grow in length and width. We know little about the regulation of these directional processes that appear as a cell gets larger with hypertrophy or smaller with atrophy. This review gives a brief overview of the regulation of cell shape and the composition and aggregation of contractile proteins into filaments, the sarcomere, and myofibrils. We examine how mechanical activity regulates the turnover and exchange of contraction proteins. Finally, we suggest what kinds of experiments are needed to answer these fundamental questions about the regulation of muscle cell shape.

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Campylobacter and helicobacter in the etiology of gastrointestinal diseases

Archives of Biological Sciences ◽

10.2298/abs1204389s ◽

2012 ◽

Vol 64 (4) ◽

pp. 1389-1404 ◽

Cited By ~ 1

Author(s):

Biljana Miljkovic-Selimovic ◽

Branislava Kocic ◽

Tatjana Babic

Keyword(s):

Bacterial Genome ◽

Optimal Growth ◽

The Elderly ◽

Distinct Species ◽

Gastrointestinal Diseases ◽

Human Pathogens ◽

Endotoxin Activity ◽

Clinical Presentations ◽

Human Disorders ◽

H Pylori

The order Campylobacterales comprises two genera: Campylobacter and Helicobacter, with a widespread distribution in both humans and animals. They are Gram-negative, spiral, helical and microaerophilic bacteria, with an optimal growth temperature of 37?C for H. pylori and 42?C for C. jejuni strains. While Helicobacter pylori are restricted to humans, other helicobacter species can be found in different mammals and occasionally in humans. Several Campylobacter species are recognized as human pathogens, while distinct species are pathogenic only occasionally, in children, the elderly and immunocompromised patients. Campylobacters and helicobacters are well adapted to the living conditions inside the gastrointestinal tract, where they can cause diseases as a consequence of inflammation. In addition, they are related to certain extraintestinal diseases, post-infectious sequels, malignancy and autoimmunity. Different clinical presentations of human disorders may be the consequences of the diversity in host immune response, bacterial genome, endotoxin activity as well as specific bacterial virulence factors.

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