Repeats-in-Toxin (RTX) proteins of Gram-negative bacteria are excreted through the type I secretion system (T1SS) that recognizes non-cleavable C-terminal secretion signals. These are preceded by arrays of glycine and aspartate-rich nonapeptide repeats grouped by four to eight β strands into blocks that fold into calcium-binding parallel β-roll structures. The β-rolls are interspersed by linkers of variable length and sequence and the organization of multiple RTX repeat blocks within large RTX domains remains unknown. Here we examined the structure and function of the RTX domain of Bordetella pertussis adenylate cyclase toxin (CyaA) that is composed of five β-roll RTX blocks. We show that the non-folded RTX repeats maintain the stability of the CyaA polypeptide in the Ca-depleted bacterial cytosol and thereby enable its efficient translocation through the T1SS apparatus. The efficacy of secretion of truncated CyaA constructs was dictated by the number of retained RTX repeat blocks and depended on the presence of extracellular Ca ions. We further describe the crystal structure of the RTX blocks IV-V of CyaA (CyaA) that consists of a contiguous assembly of two β-rolls that differs substantially from the arrangement of the RTX blocks observed in RTX lipases or other RTX proteins. These results provide a novel structural insight into the architecture of the RTX domains of large RTX proteins and support the "push-ratchet" mechanism of the T1SS-mediated secretion of very large RTX proteins.
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http://dx.doi.org/10.1016/j.jmb.2020.08.020 | DOI Listing |
Kidney Int Rep
December 2024
Department of Nephrology, Radboud institute of Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Introduction: Standard treatment with cyclophosphamide (CP) or rituximab (RTX) is suboptimal. We adapted and used the low-dose regimen used in vasculitis (RTX 2 × 1000 mg, CP 1.5 mg/kg/d × 8 weeks, and prednisone [i.
View Article and Find Full Text PDFFront Immunol
December 2024
Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
RTX was initially used for non-Hodgkin's lymphoma treatment and has been used in the clinical treatment of various autoimmune diseases as well as in antirejection and immune induction therapy for kidney transplant recipients. Following RTX treatment, the time for B cell regeneration varies among patients, but there is no unified recommendation for the frequency of B cell monitoring. This study aimed to investigate the clinical significance of periodic monitoring of peripheral blood B lymphocytes in individualized immunotherapy following rituximab (RTX) treatment in patients with different diseases.
View Article and Find Full Text PDFMed Sci Monit
December 2024
Rheumatology Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia.
BACKGROUND Rituximab (RTX) is a chimeric therapeutic monoclonal antibody that targets the CD20 molecule on B lymphocytes. RTX is approved for the treatment of rheumatoid arthritis (RA) in patients who do not respond to disease-modifying anti-rheumatic drugs (DMARDs) or other biologics. The purpose of this retrospective study was to report our experience with RTX treatment at a single center in Saudi Arabia between 2015 and 2022 in 52 patients with RA.
View Article and Find Full Text PDFPhytomedicine
December 2024
The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Department of Gastroenterology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210017, China. Electronic address:
Background: Gastroesophageal reflux disease (GERD) is a chronic condition of the digestive tract with limited therapeutic options. Bitter taste receptors (TAS2Rs) and transient receptor potential vanilloid-1 (TRPV1) are implicated in modulating inflammatory responses. Berberine (BBR) and evodiamine (EVO) are known to activate TAS2Rs and TRPV1, respectively.
View Article and Find Full Text PDFDrugs R D
December 2024
Medical Oncology, Sandoz GmbH, Holzkirchen, Germany.
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