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Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction

Death-associated protein kinase 1 (DAPK1), as a calcium/calmodulin (CaM) regulated serine/threonine kinase, functions in apoptotic and autophagy pathways and represents an interesting drug target for inflammatory bowel disease and Alzheimer’s disease. The crystal structure of the DAPK1 catalytic dom...

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Autores principales: Zhu, Yu-Ping, Gao, Xin-Yi, Xu, Guo-Hui, Qin, Zhao-Fu, Ju, Hai-Xing, Li, De-Chuan, Ma, De-Ning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599780/
https://www.ncbi.nlm.nih.gov/pubmed/36291604
http://dx.doi.org/10.3390/biom12101395
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author Zhu, Yu-Ping
Gao, Xin-Yi
Xu, Guo-Hui
Qin, Zhao-Fu
Ju, Hai-Xing
Li, De-Chuan
Ma, De-Ning
author_facet Zhu, Yu-Ping
Gao, Xin-Yi
Xu, Guo-Hui
Qin, Zhao-Fu
Ju, Hai-Xing
Li, De-Chuan
Ma, De-Ning
author_sort Zhu, Yu-Ping
collection PubMed
description Death-associated protein kinase 1 (DAPK1), as a calcium/calmodulin (CaM) regulated serine/threonine kinase, functions in apoptotic and autophagy pathways and represents an interesting drug target for inflammatory bowel disease and Alzheimer’s disease. The crystal structure of the DAPK1 catalytic domain and the autoregulatory domain (ARD) in complex with CaM provides an understanding of CaM-dependent regulation of DAPK1 activity. However, the molecular basis of how distinct Trp305 (W305Y and W305D) mutations in the ARD modulate different DAPK1 activities remains unknown. Here, we performed multiple, μs-length molecular dynamics (MD) simulations of the DAPK1–CaM complex in three different (wild-type, W305Y, and W305D) states. MD simulations showed that the overall structural complex did not change significantly in the wild-type and W305Y systems, but underwent obvious conformational alteration in the W305D system. Dynamical cross-correlation and principal component analyses revealed that the W305D mutation enhanced the anti-correlated motions between the DAPK1 and CaM and sampled a broader distribution of conformational space relative to the wild-type and W305Y systems. Structural and energetical analyses further exhibited that CaM binding was unfavored in response to the W305D mutation, resulting in the decreased binding of CaM to the W305D mutant. Furthermore, the hydrogen bonds and salt bridges responsible for the loss of CaM binding on the interface of the DAPK1–CaM complex were identified in the W305D mutant. This result may provide insights into the key role of Trp305 in the regulation of CaM-mediated DAPK1 activity.
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spelling pubmed-95997802022-10-27 Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction Zhu, Yu-Ping Gao, Xin-Yi Xu, Guo-Hui Qin, Zhao-Fu Ju, Hai-Xing Li, De-Chuan Ma, De-Ning Biomolecules Article Death-associated protein kinase 1 (DAPK1), as a calcium/calmodulin (CaM) regulated serine/threonine kinase, functions in apoptotic and autophagy pathways and represents an interesting drug target for inflammatory bowel disease and Alzheimer’s disease. The crystal structure of the DAPK1 catalytic domain and the autoregulatory domain (ARD) in complex with CaM provides an understanding of CaM-dependent regulation of DAPK1 activity. However, the molecular basis of how distinct Trp305 (W305Y and W305D) mutations in the ARD modulate different DAPK1 activities remains unknown. Here, we performed multiple, μs-length molecular dynamics (MD) simulations of the DAPK1–CaM complex in three different (wild-type, W305Y, and W305D) states. MD simulations showed that the overall structural complex did not change significantly in the wild-type and W305Y systems, but underwent obvious conformational alteration in the W305D system. Dynamical cross-correlation and principal component analyses revealed that the W305D mutation enhanced the anti-correlated motions between the DAPK1 and CaM and sampled a broader distribution of conformational space relative to the wild-type and W305Y systems. Structural and energetical analyses further exhibited that CaM binding was unfavored in response to the W305D mutation, resulting in the decreased binding of CaM to the W305D mutant. Furthermore, the hydrogen bonds and salt bridges responsible for the loss of CaM binding on the interface of the DAPK1–CaM complex were identified in the W305D mutant. This result may provide insights into the key role of Trp305 in the regulation of CaM-mediated DAPK1 activity. MDPI 2022-09-29 /pmc/articles/PMC9599780/ /pubmed/36291604 http://dx.doi.org/10.3390/biom12101395 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhu, Yu-Ping
Gao, Xin-Yi
Xu, Guo-Hui
Qin, Zhao-Fu
Ju, Hai-Xing
Li, De-Chuan
Ma, De-Ning
Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction
title Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction
title_full Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction
title_fullStr Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction
title_full_unstemmed Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction
title_short Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase–Calmodulin Interaction
title_sort computational dissection of the role of trp305 in the regulation of the death-associated protein kinase–calmodulin interaction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9599780/
https://www.ncbi.nlm.nih.gov/pubmed/36291604
http://dx.doi.org/10.3390/biom12101395
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