The regulatory role of the kinase-homology domain in receptor guanylyl cyclases: nothing ‘pseudo’ about it!

2018 ◽  
Vol 46 (6) ◽  
pp. 1729-1742 ◽  
Author(s):  
Vishwas Mishra ◽  
Ridhima Goel ◽  
Sandhya S. Visweswariah
Keyword(s):  
Protein Structures ◽  
Sequence Information ◽  
Guanylyl Cyclases ◽  
Downstream Signaling ◽  
Cyclase Domain ◽  
Interesting Possibility ◽  
Genome Sequence Information ◽  
Kinase Homology Domain ◽  
Kinase Homology

The availability of genome sequence information and a large number of protein structures has allowed the cataloging of genes into various families, based on their function and predicted biochemical activity. Intriguingly, a number of proteins harbor changes in the amino acid sequence at residues, that from structural elucidation, are critical for catalytic activity. Such proteins have been categorized as ‘pseudoenzymes’. Here, we review the role of the pseudokinase (or kinase-homology) domain in receptor guanylyl cyclases. These are multidomain single-pass, transmembrane proteins harboring an extracellular ligand-binding domain, and an intracellular domain composed of a kinase-homology domain that regulates the activity of the associated guanylyl cyclase domain. Mutations that lie in the kinase-homology domain of these receptors are associated with human disease, and either abolish or enhance cGMP production by these receptors to alter downstream signaling events. This raises the interesting possibility that one could identify molecules that bind to the pseudokinase domain and regulate the activities of these receptors, in order to alleviate symptoms in patients harboring these mutations.

Conservation of the kinaselike regulatory domain is essential for activation of the natriuretic peptide receptor guanylyl cyclases

1992 ◽  
Vol 12 (6) ◽  
pp. 2581-2590
Author(s):  
K J Koller ◽  
F J de Sauvage ◽  
D G Lowe ◽  
D V Goeddel
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Cyclase Activity ◽  
Guanylyl Cyclases ◽  
Heat Stable ◽  
Guanylyl Cyclase Activity ◽  
Kinase Homology Domain ◽  
Kinase Homology

The natriuretic peptide receptors, NPR-A and NPR-B, are two members of the newly described class of receptor guanylyl cyclases. The kinaselike domain of these proteins is an important regulator of the guanylyl cyclase activity. To begin to understand the molecular nature of this type of regulation, we made complete and partial deletions of the kinase domain in NPR-A and NPR-B. We also made chimeric proteins in which the kinase domains of NPR-A and NPR-B were exchanged or replaced with kinase domains from structurally similar proteins. Complete deletion of the kinase homology domain in NPR-A and NPR-B resulted in constitutive activation of the guanylyl cyclase. Various partial deletions of this region produced proteins that had no ability to activate the enzyme with or without hormone stimulation. The kinase homology domain can be exchanged between the two subtypes with no effect on regulation. However, structurally similar kinaselike domains, such as from the epidermal growth factor receptor or from the heat-stable enterotoxin receptor, another member of the receptor guanylyl cyclase family, were not able to regulate the guanylyl cyclase activity correctly. These findings suggest that the kinaselike domain of NPR-A and NPR-B requires strict sequence conservation to maintain proper regulation of their guanylyl cyclase activity.

scholarly journals Functional genomics of pathogenic bacteria

2002 ◽  
Vol 357 (1417) ◽  
pp. 109-116 ◽  
Author(s):  
E. R. Moxon ◽  
D. W. Hood ◽  
N. J. Saunders ◽  
E. K. H. Schweda ◽  
J. C. Richards
Keyword(s):  
Pathogenic Bacteria ◽  
Whole Genome Sequence ◽  
Sequence Information ◽  
Microbial Diseases ◽  
Mortality And Morbidity ◽  
Automated Dna Sequencing ◽  
Genome Sequence Information ◽  
Pathogenic Microbes

Microbial diseases remain the commonest cause of global mortality and morbidity. Automated–DNA sequencing has revolutionized the investigation of pathogenic microbes by making the immense fund of information contained in their genomes available at reasonable cost. The challenge is how this information can be used to increase current understanding of the biology of commensal and virulence behaviour of pathogens with particular emphasis on in vivo function and novel approaches to prevention. One example of the application of whole–genome–sequence information is afforded by investigations of the pathogenic role of Haemophilus influenzae lipopolysaccharide and its candidacy as a vaccine.

scholarly journals Conservation of the kinaselike regulatory domain is essential for activation of the natriuretic peptide receptor guanylyl cyclases.

1992 ◽  
Vol 12 (6) ◽  
pp. 2581-2590 ◽  
Author(s):  
K J Koller ◽  
F J de Sauvage ◽  
D G Lowe ◽  
D V Goeddel
Keyword(s):  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Cyclase Activity ◽  
Guanylyl Cyclases ◽  
Heat Stable ◽  
Guanylyl Cyclase Activity ◽  
Kinase Homology Domain ◽  
Kinase Homology

The natriuretic peptide receptors, NPR-A and NPR-B, are two members of the newly described class of receptor guanylyl cyclases. The kinaselike domain of these proteins is an important regulator of the guanylyl cyclase activity. To begin to understand the molecular nature of this type of regulation, we made complete and partial deletions of the kinase domain in NPR-A and NPR-B. We also made chimeric proteins in which the kinase domains of NPR-A and NPR-B were exchanged or replaced with kinase domains from structurally similar proteins. Complete deletion of the kinase homology domain in NPR-A and NPR-B resulted in constitutive activation of the guanylyl cyclase. Various partial deletions of this region produced proteins that had no ability to activate the enzyme with or without hormone stimulation. The kinase homology domain can be exchanged between the two subtypes with no effect on regulation. However, structurally similar kinaselike domains, such as from the epidermal growth factor receptor or from the heat-stable enterotoxin receptor, another member of the receptor guanylyl cyclase family, were not able to regulate the guanylyl cyclase activity correctly. These findings suggest that the kinaselike domain of NPR-A and NPR-B requires strict sequence conservation to maintain proper regulation of their guanylyl cyclase activity.

scholarly journals Building blocks of protein structures – Physics meets Biology

2020 ◽  
Author(s):  
Tatjana Skrbic ◽  
Amos Maritan ◽  
Achille Giacometti ◽  
George D. Rose ◽  
Jayanth R. Banavar
Keyword(s):  
Protein Structures ◽  
Building Blocks ◽  
Vital Role ◽  
Beta Sheets ◽  
Sequence Information ◽  
Alpha Helices ◽  
Solvent Interactions ◽  
Guiding Principle ◽  
Amino Acid Sequence Information

The native state structures of globular proteins are stable and well-packed indicating that self-interactions are favored over protein-solvent interactions under folding conditions. We use this as a guiding principle to derive the geometry of the building blocks of protein structures, alpha-helices and strands assembled into beta-sheets, with no adjustable parameters, no amino acid sequence information, and no chemistry. There is an almost perfect fit between the dictates of mathematics and physics and the rules of quantum chemistry. Our theory establishes an energy landscape that channels protein evolution by providing sequence-independent platforms for elaborating sequence-dependent functional diversity. Our work highlights the vital role of discreteness in life and has implications for the creation of artificial life and on the nature of life elsewhere in the cosmos.

scholarly journals Dermatophyte Virulence Factors: Identifying and Analyzing Genes That May Contribute to Chronic or Acute Skin Infections

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Rebecca Rashid Achterman ◽  
Theodore C. White
Keyword(s):  
Virulence Factors ◽  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Sequence Information ◽  
Skin Infections ◽  
Future Directions ◽  
Keratinized Tissue ◽  
Genome Sequence Information

Dermatophytes are prevalent causes of cutaneous mycoses and, unlike many other fungal pathogens, are able to cause disease in immunocompetent individuals. They infect keratinized tissue such as skin, hair, and nails, resulting in tinea infections, including ringworm. Little is known about the molecular mechanisms that underlie the ability of these organisms to establish and maintain infection. The recent availability of genome sequence information and improved genetic manipulation have enabled researchers to begin to identify and study the role of virulence factors of dermatophytes. This paper will summarize our current understanding of dermatophyte virulence factors and discuss future directions for identifying and testing virulence factors.

Acanthamoeba Keratitis: Current Status and Urgent Research Priorities

2019 ◽  
Vol 26 (30) ◽  
pp. 5711-5726 ◽  
Author(s):  
Naveed Ahmed Khan ◽  
Ayaz Anwar ◽  
Ruqaiyyah Siddiqui
Keyword(s):  
Rational Design ◽  
Research Priorities ◽  
Acanthamoeba Keratitis ◽  
Current Treatment ◽  
Research Literature ◽  
Current Status ◽  
Bibliographic Databases ◽  
Sequence Information ◽  
Therapeutic Measures ◽  
Genome Sequence Information

Background:First discovered in the early 1970s, Acanthamoeba keratitis has remained a major eye infection and presents a significant threat to the public health, especially in developing countries. The aim is to present a timely review of our current understanding of the advances made in this field in a comprehensible manner and includes novel concepts and provides clear directions for immediate research priorities.Methods:We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field.Results:The present review focuses on novel diagnostic and therapeutic strategies in details which can provide access to management and treatment of Acanthamoeba keratitis. This coupled with the recently available genome sequence information together with high throughput genomics technology and innovative approaches should stimulate interest in the rational design of preventative and therapeutic measures. Current treatment of Acanthamoeba keratitis is problematic and often leads to infection recurrence. Better understanding of diagnosis, pathogenesis, pathophysiology and therapeutic regimens, would lead to novel strategies in treatment and prophylaxis.

scholarly journals The possible role of Interleukin-6 as a regulator of insulin sensitivity in patients with neuromyelitis optica spectrum disorder

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhila Maghbooli ◽  
Abdorreza Naser Moghadasi ◽  
Nasim Rezaeimanesh ◽  
Abolfazl Omidifar ◽  
Tarlan Varzandi ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Neuromyelitis Optica ◽  
Serum Levels ◽  
Spectrum Disorder ◽  
Control Group ◽  
Neuromyelitis Optica Spectrum Disorder ◽  
Downstream Signaling ◽  
Reduce Insulin Sensitivity ◽  
Circulating Levels

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is associated with inflammatory mediators that may also trigger downstream signaling pathways leading to reduce insulin sensitivity. Methods We aimed to determine the risk association of hyperinsulinemia in NMOSD patients with seropositive AQP4-IgG and the serum levels of interleukin (IL)-6 and IL-17A compared with the control group. Serum levels of metabolic (Insulin, Fasting Blood Sugar (FBS), lipid profile) and inflammatory (IL-6 and IL-17) markers were assessed in 56 NMOSD patients and 100 controls. Results Hyperinsulinemia was more prevalent in NMOSD patients independent of age, sex and body mass index (BMI) (48.2% vs. 26%, p = 0.005) compared to control group. After adjusting age, sex and BMI, there was significant association between lower insulin sensitivity (IS) and NMOSD risk (95% CI: Beta = 0.73, 0.62 to 0.86, p = 0.0001). Circulating levels of IL-6 and IL-17 were higher in NMOSD patients, and only IL-6 had an effect modifier for the association between lower insulin sensitivity and NMOSD risk. Conclusions Our data suggests that inflammatory pathogenesis of NMOSD leads to hyperinsulinemia and increases the risk of insulin resistance.

scholarly journals Syndecan Transmembrane Domain Specifically Regulates Downstream Signaling Events of the Transmembrane Receptor Cytoplasmic Domain

2021 ◽  
Vol 22 (15) ◽  
pp. 7918
Author(s):  
Jisun Hwang ◽  
Bohee Jang ◽  
Ayoung Kim ◽  
Yejin Lee ◽  
Joonha Lee ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Growth Factor Receptor ◽  
Cytoplasmic Domain ◽  
Nih3t3 Cells ◽  
C Elegans ◽  
Downstream Signaling ◽  
Downstream Effectors ◽  
Signaling Events

Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains unknown. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory effects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, comprising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corresponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.

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