Mechanistic Insights into the Long-range Allosteric Regulation of KRAS Via Neurofibromatosis Type 1 (NF1) Scaffold Upon SPRED1 Loading

Li, Minyu; Wang, Yuanhao; Fan, Jigang; Zhuang, Haiming; Liu, Yaqin; Ji, Dong; Lu, Shaoyong

doi:10.1016/j.jmb.2022.167730

Cited by 19 publications

(9 citation statements)

References 97 publications

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“…To further quantitatively assess the energetics of the DAPK1–CaM interactions in the three different systems, the molecular mechanics and generalized Born surface area (MM/GBSA) binding free energy calculations were performed [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. As shown in Table 1 , the binding free energies for the WT, W305Y, and W305D systems were −116.44 ± 15.60, −118.77 ± 16.86, and −92.38 ± 17.54 kcal/mol, respectively.…”

Section: Resultsmentioning

confidence: 99%

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

Zhu

Gao

et al. 2022

Biomolecules

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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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Section: Resultsmentioning

confidence: 99%

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

Zhu

Gao

et al. 2022

Biomolecules

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“…To explore the effect of Ca 2+ removal on the allosteric network of the DAPK1–CaM complex, the difference contact network analysis (dCNA) was performed ( Li et al, 2022 ). The connected residues are considered as one community, which can be served as a synergistic functional unit of the protein.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase

et al. 2022

Front. Mol. Biosci.

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Calcium (Ca2+) signaling plays an important role in the regulation of many cellular functions. Ca2+-binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca2+/CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca2+ on the conformational dynamics of the DAPK1−CaM interactions is still unclear. Here, we performed large-scale molecular dynamics (MD) simulations of the DAPK1−CaM complex in the Ca2+-bound and-unbound states to reveal the importance of Ca2+. MD simulations revealed that removal of Ca2+ increased the anti-correlated inter-domain motions between DAPK1 and CaM, which weakened the DAPK1−CaM interactions. Binding free energy calculations validated the decreased DAPK1−CaM interactions in the Ca2+-unbound state. Structural analysis further revealed that Ca2+ removal caused the significant conformational changes at the DAPK1−CaM interface, especially the helices α1, α2, α4, α6, and α7 from the CaM and the basic loop and the phosphate-binding loop from the DAPK1. These results may be useful to understand the biological role of Ca2+ in physiological processes.

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“…To get the optimal substructure of the network, edges with the highest betweenness would be iteratively removed from the network, and the betweenness of the remaining edges would be recalculated until each node represents an isolated community. − Communities with residues less than three were dropped. We gauged the connectivity between communities by the betweenness value.…”

Section: Methodsmentioning

confidence: 99%

Markov State Models and Molecular Dynamics Simulations Reveal the Conformational Transition of the Intrinsically Disordered Hypervariable Region of K-Ras4B to the Ordered Conformation

Zhang

Fan

et al. 2022

J. Chem. Inf. Model.

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K-Ras4B, the most frequently mutated Ras isoform in human tumors, plays a vital part in cell growth, differentiation, and survival. Its tail, the C-terminal hypervariable region (HVR), is involved in anchoring K-Ras4B at the cellular plasma membrane and in isoform-specific protein–protein interactions and signaling. In the inactive guanosine diphosphate-bound state, the intrinsically disordered HVR interacts with the catalytic domain at the effector-binding region, rendering K-Ras4B in its autoinhibited state. Activation releases the HVR from the catalytic domain, with its ensemble favoring an ordered α-helical structure. The large-scale conformational transition of the HVR from the intrinsically disordered to the ordered conformation remains poorly understood. Here, we deploy a computational scheme that integrates a transition path-generation algorithm, extensive molecular dynamics simulation, and Markov state model analysis to investigate the conformational landscape of the HVR transition pathway. Our findings reveal a stepwise pathway for the HVR transition and uncover several key conformational substates along the transition pathway. Importantly, key interactions between the HVR and the catalytic domain are unraveled, highlighting the pathogenesis of K-Ras4B mild mutations in several congenital developmental anomaly syndromes. Together, these findings provide a deeper understanding of the HVR transition mechanism and the regulation of K-Ras4B activity at an atomic level.

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Mechanistic Insights into the Long-range Allosteric Regulation of KRAS Via Neurofibromatosis Type 1 (NF1) Scaffold Upon SPRED1 Loading

Cited by 19 publications

References 97 publications

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

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

Mechanistic insights into the role of calcium in the allosteric regulation of the calmodulin-regulated death-associated protein kinase

Markov State Models and Molecular Dynamics Simulations Reveal the Conformational Transition of the Intrinsically Disordered Hypervariable Region of K-Ras4B to the Ordered Conformation

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