Structural basis for type I and type II deficiencies of antithrombotic plasma protein C: Patterns revealed by three-dimensional molecular modelling of mutations of the protease domain

1994 ◽  
Vol 18 (4) ◽  
pp. 367-380 ◽  
Author(s):  
Judith S. Greengard ◽  
Cindy L. Fisher ◽  
Bruno Villoutreix ◽  
John H. Griffin
Keyword(s):  
Plasma Protein ◽  
Molecular Modelling ◽  
Protein C ◽  
Three Dimensional ◽  
Structural Basis ◽  
Type I ◽  
Type Ii ◽  
Protease Domain

Three Missense Mutations in the Protein C Heavy Chain Causing Type I and Type II Protein C Deficiency

1994 ◽  
Vol 71 (01) ◽  
pp. 032-037 ◽  
Author(s):  
Toshiyuki Miyata ◽  
Yan-Zhen Zheng ◽  
Toshiyuki Sakata ◽  
Nobuko Tsushima ◽  
Hisao Kato
Keyword(s):  
Amino Acid ◽  
Dna Sequencing ◽  
Amino Acid Substitution ◽  
Protein C ◽  
Type I ◽  
Missense Mutations ◽  
Type Ii ◽  
Protease Domain ◽  
Protein C Deficiency ◽  
Thrombin Cleavage

SummaryWe have studied the molecular basis of protein C deficiency in three families with a history of thromboembolic disease. An approximately 50% reduction in both functional and immunologic levels of protein C was detected in the plasma from two unrelated patients, designated protein C Osaka 1 and protein C Osaka 2. An approximately 50% reduction in functional level but normal immunologic level of protein C was detected in plasma from a third patient, designated protein C Osaka 3. DNA sequencing of the amplified DNA revealed one missense mutation in each case. Additional mutations in the coding sequence were excluded by DNA sequencing of all protein C exons. We identified a C-to-T change at nucleotide number 6,218 of the protein C gene in protein C Osaka 1. This results in the amino acid substitution of Arg-169 by Trp at the a-thrombin cleavage site. In protein C Osaka 2, a G-to-A change at nucleotide number 8,807 was identified leading to the amino acid substitution of Met-364 by lie in the protease domain. This substitution may impair the synthesis or stability of protein C Osaka 2. In protein C Osaka 3, a G-to-C change at nucleotide number 8,868 was identified. This results in substitution of Gly-385 by Arg in the protease domain. Based on these, it was concluded that Arg-169-to-Trp mutation and Met-364-to-Ile mutation cause type I protein C deficiency and Gly-385-to-Arg mutation causes type II deficiency.

scholarly journals Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Christopher Agnew ◽  
Pelin Ayaz ◽  
Risa Kashima ◽  
Hanna S. Loving ◽  
Prajakta Ghatpande ◽  
...  
Keyword(s):  
Md Simulations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Type I ◽  
Type Ii ◽  
Exchange Mass Spectrometry ◽  
Receptor Complexes ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Smad Proteins

AbstractUpon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

scholarly journals Altered affinity of insulin-like growth factor II (IGF-II) for receptors and IGF-binding proteins, resulting from limited modifications of the IGF-II molecule

1991 ◽  
Vol 278 (1) ◽  
pp. 249-254 ◽  
Author(s):  
Y Oh ◽  
M W Beukers ◽  
H M Pham ◽  
P A Smanik ◽  
M C Smith ◽  
...  
Keyword(s):  
Amino Acids ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Type I ◽  
Type Ii ◽  
Factor Ii ◽  
N Terminus ◽  
Severe Impairment ◽  
Igf Binding ◽  
Terminal Amino

The binding affinities of seven analogues of recombinant human insulin-like growth factor II (hIGF-II) were characterized for the IGF type-I and type-II receptors and insulin receptors, as well as for IGF-binding protein (IGFBP)-1, IGFBP-2, IGFPB-3 and human serum IGFBPs. A switch of two of the three cysteine bridges in hIGF-II, 9-47 and 46-51 to 9-46 and 47-51, severely impaired the binding of this analogue to all receptors and to the IGFBPs. The affinities for the IGF type-I receptor and the IGFBPs were decreased over 100-fold, while the binding to the insulin receptor and the IGF type-II receptor was less affected, with a 6-10-fold decrease in affinity. Slight modifications of the N-terminus had only minor effects upon the binding of hIGF-II to the IGFBPs or to the receptors. Deletion of both the N-terminal amino acid and the two C-terminal amino acids resulted in moderate decreases in affinity, with a 60% decrease in affinity for IGFBP-1 and the IGF type-I receptor. Acetylation of the N-terminus of Ala1 and the epsilon-nitrogen of Lys65 decreased the affinity, by 60-90%, of hIGF-II for all of the IGFBPs and receptors. The experiments involving acetylation of IGF-II or switching of its cysteine bridges indicated that these modifications (no substitution, deletion or addition of any of the 67 amino acids of hIGF-II) may lead to a severe impairment of the binding affinity of IGF-II for both the IGFBPs and the receptors. Acetylation of the epsilon-nitrogen of Lys65, which causes a charge change, or alteration of the three-dimensional structure, as shown by the cysteine bridge switch, lead to a severe impairment of the binding affinity for the binding proteins and for the receptors. In general, care should be taken with the synthesis of analogues and the interpretation of resulting binding data, since affinity alterations ascribed to amino acid changes may instead be caused by alterations of the charge or the three-dimensional structure of the protein.

scholarly journals Study On The Application of Preoperative Three-Dimensional CT Angiography of Perigastric Arteries In Laparoscopic Radical Gastrectomy

2022 ◽  
Author(s):  
Peng Liu ◽  
Wenbin Yu ◽  
Meng Wei ◽  
Danping Sun ◽  
Xin Zhong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Blood Loss ◽  
Three Dimensional ◽  
Classification Model ◽  
Type I ◽  
Radical Gastrectomy ◽  
Type Ii ◽  
Type Iii ◽  
Type Iv ◽  
Type V

Abstract Objection: To investigate the clinical value and significance of preoperative three-dimensional computerized tomography angiography (CTA) in laparoscopic radical gastrectomy for gastric cancer.Methods: The clinical data were analyzed retrospectively from 214 gastric cancer patients. We grouped according to whether to perform CTA. The gastric peripheral artery was classified according to CTA images of patients in the CTA group, and we compared and analyzed the difference of the data between the two groups.Results: The celiac trunk was classified according to Adachi classification: Type I (118/125, 94.4%),Type II (3/125, 2.4%),Type III (0/125, 0%),Type IV (1/125, 0.8%),Type V (2/125, 1.6%),Type VI (1/125, 0.8%).Hepatic artery classification was performed according to Hiatt classification standard:Type I (102/125, 81.6％),Type II (9/125, 7.2%),Type III (6/125, 4.8%),Type IV (2/125, 1.6%),Type V (3/125, 2.4%),Type VI (0, 0%),Others (3/125, 2.4%).And this study combined vascular anatomy and clinical surgical risk to establish a new splenic artery classification model. It was found that the operation time and estimated blood loss in the CTA group were significantly lower than those in the non-CTA group. In addition, the blood loss in the CTA group combined with ICG (Indocyanine Green) labeled fluorescence laparoscopy was significantly less than that in the group without ICG labeled. Conclusion: Preoperative CTA can objectively evaluate the vascular course and variation of patients, and then avoid the risk of operation, especially in combination with ICG labeled fluorescence laparoscopy, can further improve the quality of operation.

Possible Structural Implications of 20 Mutations in the Protein C Protease Domain

1994 ◽  
Vol 72 (06) ◽  
pp. 869-873 ◽  
Author(s):  
Judith S Greengard ◽  
John H Griffin ◽  
Cindy L Fisher
Keyword(s):  
Protein C ◽  
Three Dimensional ◽  
Protease Domain ◽  
Three Dimensional Model ◽  
Protein C Deficiency ◽  
Serine Protease Domain ◽  
Naturally Occurring ◽  
The Subject ◽  
Intensive Investigation ◽  
New Mutations

SummaryAnalysis of naturally occurring protein mutations yields valuable insights into functionally important sequences. Characterizing mutations responsible for protein C deficiency at the molecular level has been the subject of intensive investigation. In a previous study, a three-dimensional model of the serine protease domain of protein C was used to analyze the set of protease domain mutations previously available. The mutations were largely found to fall into a limited number of categories. A recently updated protein C mutation data base has provided a number of new mutations which have been analyzed for structural predictions.

scholarly journals Efficient Differentiation of Mouse Induced Pluripotent Stem Cells into Alveolar Epithelium Type II with a BRD4 Inhibitor

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Toru Momozane ◽  
Eriko Fukui ◽  
Soichiro Funaki ◽  
Makoto Fujii ◽  
Yuhei Kinehara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Protein C ◽  
Three Dimensional ◽  
Alveolar Epithelium ◽  
Type Ii ◽  
Differentiation Induction ◽  
Induced Pluripotent ◽  
Differentiation Efficiency

Regenerative medicine has continued to progress for lung biology and lung diseases. Efforts have focused on a variety of different applications for pluripotent stem cells. Several groups have reported successful methods for inducing differentiation of induced pluripotent stem cells (iPSCs) into the airway epithelium such as alveolar epithelium type II (ATII). However, differentiation efficiency varies among reports and improvements are needed. In the present paper, we propose a novel method for elimination of residual undifferentiated murine iPSCs using JQ1, a potent inhibitor of bromodomain (BRD) and extraterminal domain (BET) family proteins, for efficient differentiation into ATII. First, the murine iPSC line 20D-17 was induced to differentiate into ATII over a period of 26 days (days 0-26) using previously reported embryoid body seeding and stepwise differentiation methods. mRNA expressions of differentiation markers including surfactant protein C (Sftpc) were confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR) results, and 17% of the cells were shown positive for prosurfactant protein C (proSPC) in flow cytometry analysis. Next, those cells were cultured three-dimensionally in Matrigel for an additional 14 days (days 26-40), during which JQ1 was added for 4 days (days 28-32) to remove residual undifferentiated iPSCs. As a result, on day 40, the mRNA expression level of Sftpc in the three-dimensional culture was maintained at the same level as on day 26 and shown to be further increased by the addition of JQ1, with 39% of the cells found to express proSPC, showing that differentiation efficiency could be further increased. Three-dimensional culture with BRD4 inhibition by JQ1 improved the differentiation induction efficiency to ATII by removing residual undifferentiated murine iPSCs during the differentiation induction process.

scholarly journals The severity of developmental dysplasia of the hip does not correlate with the abnormality in pelvic incidence

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Rongshan Cheng ◽  
Muyin Huang ◽  
Willem Alexander Kernkamp ◽  
Huiwu Li ◽  
Zhenan Zhu ◽  
...  
Keyword(s):  
Pelvic Incidence ◽  
Sagittal Plane ◽  
Three Dimensional ◽  
Developmental Dysplasia ◽  
Control Group ◽  
Type I ◽  
Type Ii ◽  
Computed Tomography Images ◽  
Significant Difference ◽  
Dysplasia Of The Hip

Abstract Background The purpose of this study was to investigate the association between the severity of Developmental dysplasia of the hip (DDH) and the abnormality in pelvic incidence (PI). Methods This was a retrospective study analyzing 53 DDH patients and 53 non-DDH age-matched controls. Computed tomography images were used to construct three-dimensional pelvic model. The Crowe classification was used to classify the severity of DDH. The midpoint of the femoral head centers and sacral endplates were projected to the sagittal plane of the pelvis. The PI was defined as the angle between a line perpendicular to the sacral plate at its midpoint and a line connecting this point to the axis of the femoral heads. Independent sample t-tests were used to compare the differences between the PI of DDH group and the non-DDH controls group. Kendall’s coefficient of concordance was used to determine the correlation between the severity of DDH and PI. Results Patients with DDH had a significantly (p = 0.041) higher PI than the non-DDH controls (DDH 47.6 ± 8.2°, normal 44.2 ± 8.8°). Crowe type I patients had a significantly (p = 0.038) higher PI (48.2 ± 7.6°) than the non-DDH controls. No significant difference between the PI in Crowe type II or III patients and the PI in non-DDH controls were found (Crowe type II, 50.2 ± 9.6°, p = 0.073; Crowe type III, 43.8 ± 7.2°, p = 0.930). No correlation was found between the severity of DDH and the PI (r = 0.091, p = 0.222). Conclusions No correlation was found between the severity of DDH and the PI. The study confirmed that the PI in DDH (Crowe type I) group was higher than that of the non-DDH control group, while the PI does not correlate with the severity of DDH.

scholarly journals Preliminary Deformational Studies on a Finite Element Model of the Nasal Septum Reveals Key Areas for Septal Realignment and Reconstruction

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Kyrin Liong ◽  
Shu Jin Lee ◽  
Heow Pueh Lee
Keyword(s):  
Nasal Septum ◽  
Preoperative Planning ◽  
Three Dimensional ◽  
Element Model ◽  
Septal Cartilage ◽  
Type I ◽  
Type Ii ◽  
Anterior Nasal Spine ◽  
Force Direction ◽  
Three Dimensional Models

Background. With the current lack of clinically relevant classification methods of septal deviation, computer-generated models are important, as septal cartilage is indistinguishable on current imaging methods, making preoperative planning difficult. Methods. Three-dimensional models of the septum were created from a CT scan, and incremental forces were applied. Results. Regardless of the force direction, with increasing force, the septum first tilts (type I) and then crumples into a C shape (type II) and finally into an S shape (type III). In type I, it is important to address the dislocation in the vomer-ethmoid cartilage junction and vomerine groove, where stress is concentrated. In types II and III, there is intrinsic fracture and shortening of the nasal septum, which may be dislocated off the anterior nasal spine. Surgery aims to relieve the posterior buckling and dislocation, with realignment of the septum to the ANS and possible spreader grafts to buttress the fracture sites. Conclusion. By identifying clinically observable septal deviations and the areas of stress concentration and dislocation, a straighter, more stable septum may be achieved.

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