ArticleThe Journal of biological chemistry2009
The linker region in receptor guanylyl cyclases is a key regulatory module: mutational analysis of guanylyl cyclase C.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 52 citations in OpenAlex.
- De Novo GUCY2C and PRR12 Mutations in a Patient With Chronic Diarrhea, Small Bowel Obstructions, and Developmental Delay.ACG case reports journal · 2025Article
- Article
- Gut reactions and gut instincts: regulation of intestinal homeostasis by receptor guanylyl cyclase C (GC-C).The Biochemical journal · 2025Review
- Coupling enterotoxigenic Escherichia coli heat-stable peptide toxin with 8-arm PEG enhances immunogenicity.Journal of peptide science : an official publication of the European Peptide Society · 2025Article
- Reversal of the unique Q493R mutation increases the affinity of Omicron S1-RBD for ACE2.Computational and structural biotechnology journal · 2023Article
- Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities.Frontiers in endocrinology · 2022Review
- A genetically encoded BRET-based SARS-CoV-2 MCommunications chemistry · 2022Article
- The pseudokinase domain in receptor guanylyl cyclases.Methods in enzymology · 2022Review
- Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C.The Journal of experimental medicine · 2021Article
- In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids ofMolecules (Basel, Switzerland) · 2021Article
- Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach.American journal of medical genetics. Part A · 2021Article
- Guanylyl cyclase C as a biomarker for immunotherapies for the treatment of gastrointestinal malignancies.Biomarkers in medicine · 2021Review
- Mutational landscape of receptor guanylyl cyclase C: Functional analysis and disease-related mutations.IUBMB life · 2020Review
- Targeting Receptor Kinases in Colorectal Cancer.Cancers · 2019Review
- COMolecular and cellular biochemistry · 2018Article
- CaFrontiers in molecular neuroscience · 2018Article
- Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate.Frontiers in molecular neuroscience · 2017Article
- A novel mechanism of "metal gel-shift" by histidine-rich Ni2+-binding Hpn protein from Helicobacter pylori strain SS1.PloS one · 2017Article
- Article
- Receptor Guanylyl Cyclases in Sensory Processing.Frontiers in endocrinology · 2016Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Receptor guanylyl cyclases are multidomain proteins, and ligand binding to the extracellular domain increases the levels of intracellular cGMP. The intracellular domain of these receptors is composed of a kinase homology domain (KHD), a linker of approximately 70 amino acids, followed by the C-terminal guanylyl cyclase domain. Mechanisms by which these receptors are allosterically regulated by ligand binding to the extracellular domain and ATP binding to the KHD are not completely understood. Here we examine the role of the linker region in receptor guanylyl cyclases by a series of point mutations in receptor guanylyl cyclase C. The linker region is predicted to adopt a coiled coil structure and aid in dimerization, but we find that the effects of mutations neither follow a pattern predicted for a coiled coil peptide nor abrogate dimerization. Importantly, this region is critical for repressing the guanylyl cyclase activity of the receptor in the absence of ligand and permitting ligand-mediated activation of the cyclase domain. Mutant receptors with high basal guanylyl cyclase activity show no further activation in the presence of non-ionic detergents, suggesting that hydrophobic interactions in the basal and inactive conformation of the guanylyl cyclase domain are disrupted by mutation. Equivalent mutations in the linker region of guanylyl cyclase A also elevated the basal activity and abolished ligand- and detergent-mediated activation. We, therefore, have defined a key regulatory role for the linker region of receptor guanylyl cyclases which serves as a transducer of information from the extracellular domain via the KHD to the catalytic domain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.