Structural and functional consequences of succinate dehydrogenase subunit B mutations

Mitochondrial dysfunction, due to mutations of the gene encoding succinate dehydrogenase (SDH), has been implicated in the development of adrenal phaeochromocytomas, sympathetic and parasympathetic paragangliomas, renal cell carcinomas, gastrointestinal stromal tumours and more recently pituitary tumours. Underlying mechanisms behind germline SDH subunit B (SDHB) mutations and their associated risk of disease are not clear. To investigate genotype–phenotype correlation of SDH subunit B (SDHB) variants, a homology model for humanSDHwas developed from a crystallographic structure.SDHBmutations were mapped, and biochemical effects of these mutations were predictedin silico. Results of structural modelling indicated that many mutations withinSDHBare predicted to cause either failure of functionalSDHBexpression (p.Arg27*, p.Arg90*, c.88delC and c.311delAinsGG), or disruption of the electron path (p.Cys101Tyr, p.Pro197Arg and p.Arg242His). GFP-tagged WTSDHBand mutantSDHBconstructs were transfected (HEK293) to determine biological outcomes of these mutantsin vitro. According toin silicopredictions, specificSDHBmutations resulted in impaired mitochondrial localisation and/or SDH enzymatic activity. These results indicated strong genotype–functional correlation forSDHBvariants. This study reveals new insights into the effects ofSDHBmutations and the power of structural modelling in predicting biological consequences. We predict that our functional assessment ofSDHBmutations will serve to better define specific consequences for SDH activity as well as to provide a much needed assay to distinguish pathogenic mutations from benign variants.

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Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1α pathway in human ovarian cancer in vitro

Journal of Ovarian Research ◽

10.1186/s13048-014-0115-1 ◽

2014 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Lilan Chen ◽

Ting Liu ◽

Shu Zhang ◽

Jinhua Zhou ◽

Yunfei Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Succinate Dehydrogenase ◽

Human Ovarian Cancer ◽

Succinate Dehydrogenase Subunit B ◽

Subunit B

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Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1¿ pathway in human ovarian cancer in vitro

Journal of Ovarian Research ◽

10.1186/preaccept-8784219211432789 ◽

2014 ◽

Vol 7 (1) ◽

pp. 115 ◽

Cited By ~ 1

Author(s):

Lilan Chen ◽

Ting Liu ◽

Shu Zhang ◽

Jinhua Zhou ◽

Yunfei Wang ◽

...

Keyword(s):

Ovarian Cancer ◽

Succinate Dehydrogenase ◽

Human Ovarian Cancer ◽

Succinate Dehydrogenase Subunit B ◽

Subunit B

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Comprehensive in silico Study of GLUT10: Prediction of Possible Substrate Binding Sites and Interacting Molecules

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190613152030 ◽

2020 ◽

Vol 21 (2) ◽

pp. 117-130 ◽

Cited By ~ 1

Author(s):

Mohammad J. Hosen ◽

Mahmudul Hasan ◽

Sourav Chakraborty ◽

Ruhshan A. Abir ◽

Abdullah Zubaer ◽

...

Keyword(s):

Virtual Screening ◽

Binding Site ◽

Glucose Transporter ◽

Substrate Binding ◽

Mutation Screening ◽

Homology Model ◽

Connective Tissue Disorder ◽

Crystallographic Structure ◽

Substrate Binding Site

Objectives: The Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and stenosis of the arteries with a propensity towards aneurysm formation and dissection. It is caused by mutations in the SLC2A10 gene that encodes the facilitative glucose transporter GLUT10. The molecules transported by and interacting with GLUT10 have still not been unambiguously identified. Hence, the study attempts to identify both the substrate binding site of GLUT10 and the molecules interacting with this site. Methods: As High-resolution X-ray crystallographic structure of GLUT10 was not available, 3D homology model of GLUT10 in open conformation was constructed. Further, molecular docking and bioinformatics investigation were employed. Results and Discussion: Blind docking of nine reported potential in vitro substrates with this 3D homology model revealed that substrate binding site is possibly made with PRO531, GLU507, GLU437, TRP432, ALA506, LEU519, LEU505, LEU433, GLN525, GLN510, LYS372, LYS373, SER520, SER124, SER533, SER504, SER436 amino acid residues. Virtual screening of all metabolites from the Human Serum Metabolome Database and muscle metabolites from Human Metabolite Database (HMDB) against the GLUT10 revealed possible substrates and interacting molecules for GLUT10, which were found to be involved directly or partially in ATS progression or different arterial disorders. Reported mutation screening revealed that a highly emergent point mutation (c. 1309G>A, p. Glu437Lys) is located in the predicted substrate binding site region. Conclusion: Virtual screening expands the possibility to explore more compounds that can interact with GLUT10 and may aid in understanding the mechanisms leading to ATS.

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Hereditary pheochromocytoma/paraganglioma syndrome with a novel mutation in the succinate dehydrogenase subunit B gene in a Japanese family: two case reports

Journal of Medical Case Reports ◽

10.1186/s13256-021-02852-z ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Rei Hirose ◽

Yuya Tsurutani ◽

Chiho Sugisawa ◽

Kosuke Inoue ◽

Sachiko Suematsu ◽

...

Keyword(s):

Genetic Testing ◽

Succinate Dehydrogenase ◽

Novel Mutation ◽

Case Reports ◽

Site Mutation ◽

Japanese Family ◽

Paraganglioma Syndrome ◽

Succinate Dehydrogenase Subunit B ◽

Hereditary Pheochromocytoma ◽

Subunit B

Abstract Background Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B. Case presentation A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father’s paraganglioma tissues. In silico analysis predicted the mutation as “disease causing.” She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery. Conclusions We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.

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Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma

ANZ Journal of Surgery ◽

10.1111/j.1445-2197.2006.03855.x ◽

2006 ◽

Vol 76 (8) ◽

pp. 763-764 ◽

Cited By ~ 14

Author(s):

Mark J. Bolland ◽

Diana E. Benn ◽

Michael S. Croxson ◽

John McCall ◽

James H. F. Shaw ◽

...

Keyword(s):

Succinate Dehydrogenase ◽

Gastrointestinal Stromal Tumour ◽

Stromal Tumour ◽

Succinate Dehydrogenase Subunit B ◽

Subunit B

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P144 IN SILICO IDENTIFICATION OF PUTATITVE CLAUDIN CHANNEL BLOCKERS

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.073 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S30-S30

Author(s):

Emma Wu ◽

Priyanka Samanta ◽

Ye Li ◽

Le Shen ◽

Fatemeh Khalili ◽

...

Keyword(s):

In Silico ◽

Homology Model ◽

Docking Studies ◽

Channel Blockers ◽

Barrier Dysfunction ◽

Dynamic Simulations ◽

Epithelial Barrier Function ◽

In Vitro Measurements ◽

Potential Ligand

Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea in IBD. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that molecules that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative drugs that bind in the claudin-15 pore. AutoDock Vina (Scripps Research Institute) was initially used to assess rigid docking using small molecule ligand databases. The ligands were analyzed based on binding affinity to the pore and visualized using VMD (University of Illinois at Urbana-Champaign) for their potential blockage of the channel. Overall, a total of eight candidate ligands from the databases were identified: three from the UICentre database of 10000 ligands, one chemically similar structure identified in another online database (Chemspider), and four which are modifications on the chemical structure generated using ChemDraw. The analysis revealed that the eight ligands were docked in two predominant positions. In the first position, the ligands with more rings docked in an almost linear fashion and interacted with both D55 and D64 pore residues. In the second position of binding, the ligands were more flexible and could hence fold to interact only with D55 residues, thus biding predominantly in the center of the pores. To further evaluate these ligands, we will now turn to 1) flexible claudin-15 docking studies, 2) molecular dynamic simulations and, 3) in vitro measurements using monolayers induced to express claudin -15 and claudin-15 mutants. We also developed a claudin-2 homology model on which we will perform docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Finally, other databases will be analyzed for potential ligand blockers of claudin-2 and -15.

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