Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosis
Identification of new effective inhibitors of apoptosis is an important task for drug development for treatment of a number diseases including neurogenerative diseases. Initiation of apoptosis occurs via the formationof macromolecular protein complexes. In these complexes, activation of key enzymes...
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| Format: | Article |
| Language: | English |
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Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders
2016-01-01
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| Series: | Вавиловский журнал генетики и селекции |
| Subjects: | |
| Online Access: | https://vavilov.elpub.ru/jour/article/view/491 |
| _version_ | 1797214166875897856 |
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| author | N. V. Ivanisenko I. N. Lavrik V. A. Ivanisenko |
| author_facet | N. V. Ivanisenko I. N. Lavrik V. A. Ivanisenko |
| author_sort | N. V. Ivanisenko |
| collection | DOAJ |
| description | Identification of new effective inhibitors of apoptosis is an important task for drug development for treatment of a number diseases including neurogenerative diseases. Initiation of apoptosis occurs via the formationof macromolecular protein complexes. In these complexes, activation of key enzymes in apoptosis, caspases, takes place. One of those macromolecular complexes is DISC (death- inducing signaling complex) playing a central role in the induction of the extrinsic apoptosis pathway. The adaptor protein FA DD has a major role in the formation of the DISC. Therefore, inhibitors of FA DD, preventing its function in the DISC, can act as potential drugs inhibiting apoptosis. Furthermore, the study of the mechanisms of action of these inhibitors is of great interest for understanding the mechanisms of the signal transduction pathways of apoptosis. It has been reported that a natural protein inhibitor of FA DD is mucin-type 1 glycoprotein (MUC1). In particular, two fragments of the primary structure of the cytoplasmic domain of MUC1 (MUC1- CD) are capable of inhibiting the binding of caspase-8 to FA DD. However, the three-dimensional structure of MUC1 has not been obtained yet. It complicates significantly the rational design of potential drugs on the basis of these peptides. In this context, the aim of the present study was in silico prediction ofthree-dimensional structures of MUC1-CD peptides corresponding to protein fragments (1-20 and 46-72), as well as analysis of their conformational properties. The main focus of the work was given to the peptide MUC1-CD (46-72), which is capable of binding to FA DD. Using the methods of molecular dynamics in the implicit water it was shown that the peptide MUC1-CD (46-72) can take conformations similar to the conformations of a number of fragments of the caspase-8 DED domain. It was found that the structure of the peptide MUC1-CD (46-72) is similar to the spatial structure of at least four fragments of caspase-8. These results indicate that the molecular mechanism of the inhibitory activity of the peptide can be explained by competitive binding with FA DD due to the structural and conformational similarity with the fragments of the caspase-8 DED domain. |
| first_indexed | 2024-03-07T16:07:23Z |
| format | Article |
| id | doaj.art-aba0a28ed9764ebb8cd7cf0cef48dc8b |
| institution | Directory Open Access Journal |
| issn | 2500-3259 |
| language | English |
| last_indexed | 2024-04-24T11:09:52Z |
| publishDate | 2016-01-01 |
| publisher | Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders |
| record_format | Article |
| series | Вавиловский журнал генетики и селекции |
| spelling | doaj.art-aba0a28ed9764ebb8cd7cf0cef48dc8b2024-04-11T15:30:56ZengSiberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and BreedersВавиловский журнал генетики и селекции2500-32592016-01-0119673173710.18699/VJ15.101434Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosisN. V. Ivanisenko0I. N. Lavrik1V. A. Ivanisenko2Institute of Cytology and Genetics SB RA S, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, RussiaInstitute of Cytology and Genetics SB RA S, Novosibirsk, Russia Department of Translational Inflammation, Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, GermanyInstitute of Cytology and Genetics SB RA S, Novosibirsk, RussiaIdentification of new effective inhibitors of apoptosis is an important task for drug development for treatment of a number diseases including neurogenerative diseases. Initiation of apoptosis occurs via the formationof macromolecular protein complexes. In these complexes, activation of key enzymes in apoptosis, caspases, takes place. One of those macromolecular complexes is DISC (death- inducing signaling complex) playing a central role in the induction of the extrinsic apoptosis pathway. The adaptor protein FA DD has a major role in the formation of the DISC. Therefore, inhibitors of FA DD, preventing its function in the DISC, can act as potential drugs inhibiting apoptosis. Furthermore, the study of the mechanisms of action of these inhibitors is of great interest for understanding the mechanisms of the signal transduction pathways of apoptosis. It has been reported that a natural protein inhibitor of FA DD is mucin-type 1 glycoprotein (MUC1). In particular, two fragments of the primary structure of the cytoplasmic domain of MUC1 (MUC1- CD) are capable of inhibiting the binding of caspase-8 to FA DD. However, the three-dimensional structure of MUC1 has not been obtained yet. It complicates significantly the rational design of potential drugs on the basis of these peptides. In this context, the aim of the present study was in silico prediction ofthree-dimensional structures of MUC1-CD peptides corresponding to protein fragments (1-20 and 46-72), as well as analysis of their conformational properties. The main focus of the work was given to the peptide MUC1-CD (46-72), which is capable of binding to FA DD. Using the methods of molecular dynamics in the implicit water it was shown that the peptide MUC1-CD (46-72) can take conformations similar to the conformations of a number of fragments of the caspase-8 DED domain. It was found that the structure of the peptide MUC1-CD (46-72) is similar to the spatial structure of at least four fragments of caspase-8. These results indicate that the molecular mechanism of the inhibitory activity of the peptide can be explained by competitive binding with FA DD due to the structural and conformational similarity with the fragments of the caspase-8 DED domain.https://vavilov.elpub.ru/jour/article/view/491apoptosisprogrammed cell deathfa ddmuc1caspase-8molecular dynamicsimplicit salvationgeneralized born modelprotein structure prediction |
| spellingShingle | N. V. Ivanisenko I. N. Lavrik V. A. Ivanisenko Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosis Вавиловский журнал генетики и селекции apoptosis programmed cell death fa dd muc1 caspase-8 molecular dynamics implicit salvation generalized born model protein structure prediction |
| title | Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosis |
| title_full | Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosis |
| title_fullStr | Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosis |
| title_full_unstemmed | Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosis |
| title_short | Computer simulation of the spatial structure of MUC 1 peptides capable of inhibiting apoptosis |
| title_sort | computer simulation of the spatial structure of muc 1 peptides capable of inhibiting apoptosis |
| topic | apoptosis programmed cell death fa dd muc1 caspase-8 molecular dynamics implicit salvation generalized born model protein structure prediction |
| url | https://vavilov.elpub.ru/jour/article/view/491 |
| work_keys_str_mv | AT nvivanisenko computersimulationofthespatialstructureofmuc1peptidescapableofinhibitingapoptosis AT inlavrik computersimulationofthespatialstructureofmuc1peptidescapableofinhibitingapoptosis AT vaivanisenko computersimulationofthespatialstructureofmuc1peptidescapableofinhibitingapoptosis |