Molecular mechanism of pH-dependent substrate transport by an arginine-agmatine antiporter

Wang, Sheng; Yan, Renhong; Zhang, Xi; Chu, Q.; Shi, Yigong

doi:10.1073/pnas.1414093111

Cited by 22 publications

(26 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The free energy of Arg decarboxylation drives the continuous pumping of protons out of the cell (3). Studies on the molecular genetics (4,5), protein biochemistry (2,3), transport function (2,3,6,7), and structure (2,(8)(9)(10)(11) of AdiC have enriched our understanding of this protein. The four reported 3D AdiC structures consist of 12 transmembrane α-helices (TMs) and are in the outward-open, substrate-free (8,9), outward-open, Arg-bound (11), and outward-facing occluded Arg-bound states (10).…”

mentioning

confidence: 99%

Insights into the molecular basis for substrate binding and specificity of the wild-type L-arginine/agmatine antiporter AdiC

İlgü

Jeckelmann

Gapsys

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

View full text Add to dashboard Cite

Pathogenic enterobacteria need to survive the extreme acidity of the stomach to successfully colonize the human gut. Enteric bacteria circumvent the gastric acid barrier by activating extreme acidresistance responses, such as the arginine-dependent acid resistance system. In this response, L-arginine is decarboxylated to agmatine, thereby consuming one proton from the cytoplasm. In Escherichia coli, the L-arginine/agmatine antiporter AdiC facilitates the export of agmatine in exchange of L-arginine, thus providing substrates for further removal of protons from the cytoplasm and balancing the intracellular pH. We have solved the crystal structures of wild-type AdiC in the presence and absence of the substrate agmatine at 2.6-Å and 2.2-Å resolution, respectively. The high-resolution structures made possible the identification of crucial water molecules in the substrate-binding sites, unveiling their functional roles for agmatine release and structure stabilization, which was further corroborated by molecular dynamics simulations. Structural analysis combined with site-directed mutagenesis and the scintillation proximity radioligand binding assay improved our understanding of substrate binding and specificity of the wild-type L-arginine/agmatine antiporter AdiC. Finally, we present a potential mechanism for conformational changes of the AdiC transport cycle involved in the release of agmatine into the periplasmic space of E. coli. membrane protein | scintillation proximity assay | substrate binding | transporter | X-ray structure

show abstract

mentioning

confidence: 99%

Insights into the molecular basis for substrate binding and specificity of the wild-type L-arginine/agmatine antiporter AdiC

İlgü

Jeckelmann

Gapsys

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

View full text Add to dashboard Cite

show abstract

“…The Arg residues scattered over the surface of the fibronectin III-like (FnIII) domain of a β-glucosidase play an important role in the interaction with lignin by means of cation-π stacking with the aromatic rings28. Additionally, the aromatic side chain of Tyr74 in the amino acid antiporter AdiC is a critical pH sensor that is mediated by cation-π interaction29. However, the contribution is currently unknown with respect to cation-π interaction’s role in the catalytic performance of enzymes.…”

Section: Discussionmentioning

confidence: 99%

Probing the role of cation-π interaction in the thermotolerance and catalytic performance of endo-polygalacturonases

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Understanding the dynamics of the key pectinase, polygalacturonase, and improving its thermotolerance and catalytic efficiency are of importance for the cost-competitive bioconversion of pectic materials. By combining structure analysis and molecular dynamics (MD) simulations, eight mutagenesis sites having the potential to form cation-π interactions were identified in the widely used fungal endo-polygalacturonase PG63. In comparison to the wild-type, three single mutants H58Y, T71Y and T304Y showed improved thermostability (the apparent Tms increased by 0.6−3.9 °C) and catalytic efficiency (by up to 32-fold). Chromatogram analysis of the hydrolysis products indicated that a larger amount of shorter sugars were released from the polygalacturonic acid by these three mutants than by the wild-type. MD analysis of the enzyme-substrate complexes illustrated that the mutants with introduced cation-π interaction have modified conformations of catalytic crevice, which provide an enviable environment for the catalytic process. Moreover, the lower plasticity of T3 loop 2 at the edge of the subsite tunnel appears to recruit the reducing ends of oligogalacturonide into the active site tunnel and initiates new hydrolysis reactions. This study demonstrates the importance of cation-π interaction in protein conformation and provides a realistic strategy to enhance the thermotolerance and catalytic performance of endo-polygalacturonases.

show abstract

“…As a result of extensive carbon dioxide and lactic acid production, cancer cells are constantly experiencing acid-base fluxes, which severely [16]. These specialized proteins are able to induce pH changes by facilitating new interactions or eliminating others [17]. Cancer cells need substantial input of energy for their ever-increasing metabolic demand.…”

Section: Chemistry Pathophysiology and Staging Of Breast Cancermentioning

confidence: 99%

Targeted Breast Cancer Treatment Using New Photochemotherapeutic Compounds

Tynga¹,

Abrahamse²

2020

Breast Cancer Biology

View full text Add to dashboard Cite

The deregulation of cell growth in milk-producing glands, milk-carrying tubes, or connective tissues is known as breast cancer. It originates from genetic mutations and has the ability to metastasize. Primary tumor cells repetitively divide and lead to inappropriate mechanisms, tumorigenesis, and carcinogenesis, characterized by improper cell type, function, lifetime, and self-destruction. The tumor-specific activation is considered to be an effective strategy for selective cancer destruction, which remains an issue with conventional therapeutic approaches. The tumor microenvironment can be regulated and adapted through an interaction between pH, proteins, and other factors. Principally, human breast cancer genes, BRCA1 and BRCA2, produce tumor suppressors that prevent changes in genetic materials, as well as ensure their stability. Photodynamic therapy is a targeted cancer modality that depends on the photochemotherapeutic agent and light characteristics used to activate the compound. The possibility of eradicating breast cancer depends on continuous development of therapeutic approaches using third-generation photochemotherapeutic compounds to improve targeting this cancer and its stem cells.

show abstract

Molecular mechanism of pH-dependent substrate transport by an arginine-agmatine antiporter

Cited by 22 publications

References 24 publications

Insights into the molecular basis for substrate binding and specificity of the wild-type L-arginine/agmatine antiporter AdiC

Insights into the molecular basis for substrate binding and specificity of the wild-type L-arginine/agmatine antiporter AdiC

Probing the role of cation-π interaction in the thermotolerance and catalytic performance of endo-polygalacturonases

Targeted Breast Cancer Treatment Using New Photochemotherapeutic Compounds

Contact Info

Product

Resources

About