Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases
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| Creator |
Banerjee, Antara
Chakraborty, Subhadip Chakraborty, Abhijit Chakrabarti, Saikat Ray, Kunal |
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| Subject |
Molecular & Human Genetics
Structural Biology & Bioinformatics |
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| Description |
Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell
based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or
very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover
rate. We performed extensive normal mode analysis and molecular-dynamics-simulationsbased structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis,and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological
activities of CYP1B1 for correlation with congenital and adult onset glaucomas.
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| Date |
2016-05
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2531/1/PLOS_ONE.pdf
Banerjee, Antara and Chakraborty, Subhadip and Chakraborty, Abhijit and Chakrabarti, Saikat and Ray, Kunal (2016) Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases. PLOS ONE May 31, 2016. 01p. -30p.. |
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| Relation |
http://dx.doi.org/10.1371/journal.pone.0156252
http://www.eprints.iicb.res.in/2531/ |
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