Modeling effects of mutations in coiled-coil structures: Case study using epidermolysis bullosa simplex mutations in segment 1a of k5/k14 intermediate filaments
The sequence of a protein chain determines both its conformation and its function in vivo. An attempt is made to gain an understanding of the classes of deformations that can arise in an important structural motif, the α‐helical coiled coil, as a consequence of mutations occurring in its underlying...
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Published in | Proteins, structure, function, and bioinformatics Vol. 55; no. 4; pp. 1043 - 1052 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.06.2004
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Subjects | |
Online Access | Get full text |
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Summary: | The sequence of a protein chain determines both its conformation and its function in vivo. An attempt is made to gain an understanding of the classes of deformations that can arise in an important structural motif, the α‐helical coiled coil, as a consequence of mutations occurring in its underlying heptad substructure. In order to do so we consider the model structure of segment 1A in intermediate filaments and then investigate the structures arising from each of the 22 mutations observed in cytokeratin K5/K14 molecules that lead to variants of epidermolysis bullosa simplex. These are refined separately using a molecular dynamics protocol. The mutations often result in a significant distortion of the backbone over a turn or so of the α helix in either the chain itself or its constituent partner, leading to the likelihood of impaired chain aggregation and hence molecular assembly. One mutant (K14‐L143P; 1A‐28) gave rise to structural distortion along almost the entire length of segment 1A. The remaining structures showed less deformation, and normal‐looking intermediate filaments are likely in vivo. In addition, an identical mutation in the same position in each of the chains in the heterodimer did not necessarily give equivalent structural distortions. Although proline mutations frequently lead to the most severe structural deformations, a non‐proline substitution (K14‐R125S; 1A‐10) gave rise to the largest local structural disruption that was observed. Unexpectedly, mutations in positions a and d were not always of the greatest structural significance, although three in position a were shown by AGADIR to result in a significant increase in α‐helix stability. Proteins 2004. © 2004 Wiley‐Liss, Inc. |
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Bibliography: | ArticleID:PROT20089 ark:/67375/WNG-CVB08JD2-5 Marsden - No. MAU 903 and MAU 101 istex:0BABC84971ACF45D90B341F73BEC0F837BBC12DA The second author passed away 7 April 2003. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0887-3585 1097-0134 |
DOI: | 10.1002/prot.20089 |