التفاصيل البيبلوغرافية
| العنوان: |
Structural consequences of hereditary spastic paraplegia disease-related mutations in kinesin. |
| المؤلفون: |
Dutta, Mandira, Diehl, Michael R., Onuchic, José N., Jana, Biman |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America; 11/13/2018, Vol. 115 Issue 46, pE10822-E10822, 8p |
| مصطلحات موضوعية: |
PARAPLEGIA, KINESIN, MECHANICAL chemistry, MICROTUBULE-associated protein kinase, DIMERIZATION |
| مستخلص: |
A wide range of mutations in the kinesin motor Kif5A have been linked to a neuronal disorder called hereditary spastic paraplegia (HSP). The position of these mutations can vary, and a range of different motile behaviors have been observed, indicating that the HSP mutants can alter distinct aspects of kinesin mechanochemistry. While focusing on four key HSP-associated mutants, this study examined the structural and dynamic perturbations that arise from these mutations using a series of different computational methods, ranging from bioinformatics analyses to all-atom simulations, that account for solvent effects explicitly. We show that two catalytic domain mutations (R280S and K253N) reduce the microtubule (MT) binding affinity of the kinesin head domains appreciably, while N256S has a much smaller impact. Bioinformatics analysis suggests that the stalk mutation A361V perturbs motor dimerization. Subsequent integration of these effects into a coarse-grained structure-based model of dimeric kinesin revealed that the order-disorder transition of the neck linker is substantially affected, indicating a hampered directionality and processivity of kinesin. The present analyses therefore suggest that, in addition to kinesin-MT binding and coiled-coil dimerization, HSP mutations affecting motor stepping transitions and processivity can lead to disease. [ABSTRACT FROM AUTHOR] |
|
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
