Please use this identifier to cite or link to this item: https://doi.org/10.1111/boc.201700061
Title: Mechanical Responses of the Mechanosensitive Unstructured Domains in Cardiac Titin
Authors: Pang Si Ming
LE SHIMIN 
YAN JIE 
Keywords: Cardiac titin
Magnetic tweezers
Mechanosensing
N2B
PEVK
Issue Date: 11-Dec-2017
Publisher: Chichester : Wiley-Blackwell
Citation: Pang Si Ming, LE SHIMIN, YAN JIE (2017-12-11). Mechanical Responses of the Mechanosensitive Unstructured Domains in Cardiac Titin. Biology of the cell 110 (3) : 65-76. ScholarBank@NUS Repository. https://doi.org/10.1111/boc.201700061
Abstract: Background Information. Titin is one of the three main filaments in cardiac sarcomere. Besides a chain of Ig domains, cardiac titin also contains a proline (P), glutamate (E), valine (V), lysine (K) (PEVK) domain and a cardiacspecific N2B domain, both are largely unstructured. While they are believed to be involved in the elastic (PEVK and N2B) and the trophic (N2B) functions of the heart, their mechanical responses in physiological level of forces remains poorly understood. Results. In order to gain understanding on their mechanical responses, we used magnetic tweezers to investigate their force responses from 1 to 30 pN. We confirmed that in vitro the PEVK domain is intrinsically disordered within the force range. Surprisingly, we discovered a mechanosensitive folded element in the disordered region of N2B, 84 amino acids in length, which has a large folding energy of approximately −10 kBT. Based on the force responses of PEVK and N2B domains, as well as an approximated force-dependent unfolding and refolding rates of titin Ig domains, we show that the tension in cardiac titin fluctuates within 5 pN during cardiac contraction and extension cycle using Gillespie simulation algorithm. Exceptionally, the simulation shows that deletion of N2B domain results in 10-fold increase in peak force. Conclusion. Our results highlight a critical role that N2B may potentially play in regulating tension on cardiac titin. Significance. The study provides new insights into the tension regulatory role of unstructured domains in the elastic function of the heart, which has broad implication in diastolic dysfunction and cardiac trophic mechanisms. In addition, the method can be applied to probing other unstructured mechanosensitive proteins/domains.
Source Title: Biology of the cell
URI: https://scholarbank.nus.edu.sg/handle/10635/170839
ISSN: 1768-322X
0248-4900
DOI: 10.1111/boc.201700061
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