Probing the Structure and Function of Human Glutaminase-Interacting Protein: A Possible Target for Drug Design†‡

AbstractIn eukaryotes, histones and their variants are essential for chromatin structure and function; both play important roles in the regulation of gene transcription, as well as the development of tumors. We aimed to explore the genomics data of hepatocellular carcinoma (HCC), combined with literature analysis, in terms of the histone variant H2A.Z. Cell phenotype assay confirmed the effect of H2A.Z on the proliferation, metastasis, apoptosis, and cell cycle of HCC cells. H2A.Z was shown to function via the tumor dysregulation signaling pathway, with BCL6 as its interacting protein. In addition, the acetylation level of H2A.Z was higher in HCC and was related to tumor formation. We found the acetylation of H2A.Z to be related to and regulated by lincZNF337-AS1. LincZNF337-AS1 was found to bind to H2A.Z and KAT5 at different sites, promoting the acetylation of H2A.Z through KAT5. We concluded that, in HCC, H2A.Z is an oncogene, whose acetylation promotes the transcription of downstream genes, and is regulated by lincZNF331-AS1.

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Heterogeneity of autoantibodies to factor VIII: differences in specificity for apparently distinct antigenic determinants of factor VIII coagulant protein

Blood ◽

10.1182/blood.v62.1.133.bloodjournal621133 ◽

1983 ◽

Vol 62 (1) ◽

pp. 133-140 ◽

Cited By ~ 7

Author(s):

MP Croissant ◽

M Zuzel ◽

JP Allain

Keyword(s):

Factor Viii ◽

Protein A ◽

Structure And Function ◽

Selective Recognition ◽

Antigenic Determinants ◽

Immunoradiometric Assay ◽

Naturally Occurring ◽

Response Slope ◽

And Function ◽

Naturally Occurring Antibodies

The interference of antibodies to factor VIII coagulant protein (VIII:C) of 9 nonhemophilic patients with the binding to factor VIII coagulant antigen (VIII:CAg) of a reference hemophilic 125I-Fab' reagent, used in a liquid phase VIII:CAg assay, was studied. The binding competition was estimated from immunoradiometric assay (IRMA) dose-response slope of VIII:CAg present in patient plasma, interference of antibodies with the 125I-Fab' binding to VIII:CAg in normal plasma, and the displacement of antibody from the complexes with VIII:CAg by the 125I Fab'. Antibody populations from three patients were studied in detail; in the VIII:CAg assay, two of them interfered with the 125I- Fab' binding, and one did not (patient 1). The formation of stable complexes between antibodies of each patient and VIII:CAg was demonstrated by protein-A-Sepharose adsorption. The 125I-Fab' binding to VIII:CAg-anti-VIII:CAg IgG complexes indicated that patient 1 antibodies and the 125I-Fab' recognized different antigenic determinants, whereas the other two patient antibodies and 125I-Fab' recognized closely related or identical VIII:CAg determinants. These results demonstrate an apparently selective recognition of at least two distinct VIII:CAg determinants by naturally occurring antibodies, suggesting a possibility of a wider use of these antibodies in studies of the structure and function of factor VIII.

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Pneumococcal Virulence Factors: Structure and Function

Microbiology and Molecular Biology Reviews ◽

10.1128/mmbr.65.2.187-207.2001 ◽

2001 ◽

Vol 65 (2) ◽

pp. 187-207 ◽

Cited By ~ 289

Author(s):

Mark J. Jedrzejas

Keyword(s):

Virulence Factors ◽

Surface Antigen ◽

Pneumococcal Disease ◽

Protein A ◽

The Elderly ◽

Structure And Function ◽

Structural Level ◽

Hyaluronate Lyase ◽

Antigen A ◽

And Function

SUMMARY The overall goal for this review is to summarize the current body of knowledge about the structure and function of major known antigens of Streptococcus pneumoniae, a major gram-positive bacterial pathogen of humans. This information is then related to the role of these proteins in pneumococcal pathogenesis and in the development of new vaccines and/or other antimicrobial agents. S. pneumoniae is the most common cause of fatal community-acquired pneumonia in the elderly and is also one of the most common causes of middle ear infections and meningitis in children. The present vaccine for the pneumococcus consists of a mixture of 23 different capsular polysaccharides. While this vaccine is very effective in young adults, who are normally at low risk of serious disease, it is only about 60% effective in the elderly. In children younger than 2 years the vaccine is ineffective and is not recommended due to the inability of this age group to mount an antibody response to the pneumococcal polysaccharides. Antimicrobial drugs such as penicillin have diminished the risk from pneumococcal disease. Several pneumococcal proteins including pneumococcal surface proteins A and C, hyaluronate lyase, pneumolysin, autolysin, pneumococcal surface antigen A, choline binding protein A, and two neuraminidase enzymes are being investigated as potential vaccine or drug targets. Essentially all of these antigens have been or are being investigated on a structural level in addition to being characterized biochemically. Recently, three-dimensional structures for hyaluronate lyase and pneumococcal surface antigen A became available from X-ray crystallography determinations. Also, modeling studies based on biophysical measurements provided more information about the structures of pneumolysin and pneumococcal surface protein A. Structural and biochemical studies of these pneumococcal virulence factors have facilitated the development of novel antibiotics or protein antigen-based vaccines as an alternative to polysaccharide-based vaccines for the treatment of pneumococcal disease.

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Structure and function of vaccinia virus thymidine kinase: Biomedical relevance and implications for antiviral drug design

Reviews in Medical Virology ◽

10.1002/rmv.1980010407 ◽

1991 ◽

Vol 1 (4) ◽

pp. 235-245 ◽

Cited By ~ 3

Author(s):

Margaret E. Black ◽

Dennis E. Hruby

Keyword(s):

Drug Design ◽

Vaccinia Virus ◽

Thymidine Kinase ◽

Antiviral Drug ◽

Structure And Function ◽

And Function

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Polymerase Delta Interacting Protein 2 Sustains Vascular Structure and Function

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.113.301913 ◽

2013 ◽

Vol 33 (9) ◽

pp. 2154-2161 ◽

Cited By ~ 40

Author(s):

Roy L. Sutliff ◽

Lula L. Hilenski ◽

Angélica M. Amanso ◽

Ioannis Parastatidis ◽

Anna E. Dikalova ◽

...

Keyword(s):

Structure And Function ◽

Vascular Structure ◽

Interacting Protein ◽

And Function

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P5998The Phosphodiesterase 4D interacting protein averts volume overload - but not pressure overload-induced pathological myocardial remodeling

European Heart Journal ◽

10.1093/eurheartj/ehz746.0719 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

B A Mohamed ◽

M Elkenani ◽

J Jakubiczka-Smorag ◽

M Bader ◽

G Hasenfuss ◽

...

Keyword(s):

Pressure Overload ◽

Mortality Rates ◽

Structure And Function ◽

Cardiac Structure ◽

Myocardial Remodeling ◽

Interacting Protein ◽

Protein Levels ◽

Cardiac Structure And Function ◽

And Function ◽

Phosphodiesterase 4D

Abstract Background Although volume- and pressure-overload (VO and PO, respectively) are hemodynamic stress, each results in distinct phenotypes. The Phosphodiesterase 4D interacting protein (PDE4DIP) is a protein involved in cardiac muscle contraction and suggested to play a role in cardiomyopathy. We previously identified Pde4dip transcript as being downregulated in VO but upregulated in PO. Objective We wanted to address whether Pde4dip deletion would alter the progression of pathological myocardial remodeling and heart failure (HF) following hemodynamic stress. Methods Pde4dip knockout (Pde4dip-KO) and age- and sex-matched wild-type (WT) mice were exposed to aortocaval shunt-triggered VO or transthoracic aortic constriction (TAC)-induced PO. Mortality rates were assessed and the cardiac structure and function were determined by serial echocardiography. Results The PDE4DIP protein levels decreased significantly in volume-overloaded hearts. However, pressure-overloaded hearts did not alter PDE4DIP protein levels, suggesting different posttranscriptional modifications that might affect the PDE4DIP protein expression in VO versus PO. The Pde4dip-KO Hearts were structurally and functionally normal in echocardiographic and morphometric analyses. However, Pde4dip deletion mildly attenuated the mortality rates in shunt-, but not in TAC-operated mice. A significant deterioration of left ventricle geometry and function was observed in volume-overloaded WT hearts at 12 weeks after shunt, but preserved cardiac function were noticed in shunt-operated Pde4dip-KO mice. On the other hand, TAC-operated WT and Pde4dip-KO mice exhibited a significant, but comparable deterioration of cardiac structure and function compared to sham mice. Conclusion Here we identified the PDE4DIP as an essential regulator of pathological myocardial remodeling following VO, but irrelevant to the development of cardiac dysfunction after TAC. Further investigations are warranted to dissect the possible mechanisms underlying the protective role of PDE4DIP deletion in the setting of VO. Acknowledgement/Funding This work was supported by DFG (SFB1002 project D04 to KT and D01 to GH; IRTG1816 to ME); BAM was funded by DSHF

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