| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Das Dhaked, Bhagwan Anoop, Arunagiri Jha, Narendra Nath Ghosh, Saikat Das, Subhadeep Singru, Praful Kombrabail, Mamata Kumar, Ashutosh Pratihar, Supriya Padinhateeri, Ranjith Bhaumik, Prasenjit Agarwal, Kumud Kumar, Santosh Maji, Samir K. Ranganathan, Srivastav Sahay, Shruti Jacob, Reeba S. |
| Description |
Author Affiliation: Anoop A ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Ranganathan S ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Das Dhaked B ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Jha NN ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Pratihar S ( the Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai 400 005.); Ghosh S ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Sahay S ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Kumar S ( the School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar 751 005, and.); Das S ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076, the IITB-Monash Research Academy, Indian Institute of Technology Bombay, Mumbai 400 076, India.); Kombrabail M ( the Department of Chemical Sciences, Tata Institute of Fundamental Research, Mumbai 400 005.); Agarwal K ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Jacob RS ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Singru P ( the School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar 751 005, and.); Bhaumik P ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Padinhateeri R ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076.); Kumar A ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076, ashutoshk@iitb.ac.in.); Maji SK ( From the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400 076, samirmaji@iitb.ac.in.) |
| Abstract |
The storage of protein/peptide hormones within subcellular compartments and subsequent release are crucial for their native function, and hence these processes are intricately regulated in mammalian systems. Several peptide hormones were recently suggested to be stored as amyloids within endocrine secretory granules. This leads to an apparent paradox where storage requires formation of aggregates, and their function requires a supply of non-aggregated peptides on demand. The precise mechanism behind amyloid formation by these hormones and their subsequent release remain an open question. To address this, we examined aggregation and fibril reversibility of a cyclic peptide hormone somatostatin (SST)-14 using various techniques. After proving that SST gets stored as amyloid in vivo, we investigated the role of native structure in modulating its conformational dynamics and self-association by disrupting the disulfide bridge (Cys(3)-Cys(14)) in SST. Using two-dimensional NMR, we resolved the initial structure of somatostatin-14 leading to aggregation and further probed its conformational dynamics in silico. The perturbation in native structure (S-S cleavage) led to a significant increase in conformational flexibility and resulted in rapid amyloid formation. The fibrils formed by disulfide-reduced noncyclic SST possess greater resistance to denaturing conditions with decreased monomer releasing potency. MD simulations reveal marked differences in the intermolecular interactions in SST and noncyclic SST providing plausible explanation for differential aggregation and fibril reversibility observed experimentally in these structural variants. Our findings thus emphasize that subtle changes in the native structure of peptide hormone(s) could alter its conformational dynamics and amyloid formation, which might have significant implications on their reversible storage and secretion. |
| ISSN |
00219258 |
| e-ISSN |
1083351X |
| Journal |
Journal of Biological Chemistry |
| Issue Number |
24 |
| Volume Number |
289 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date |
2014-06-13 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Amyloid Chemistry Disulfides Exocytosis Somatostatin Amino Acid Sequence Metabolism Animals Hypothalamus Molecular Dynamics Simulation Molecular Sequence Data Polymerization Protein Conformation Secretory Vesicles Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
