The dynamic nature of the K-Ras/calmodulin complex can be altered by oncogenic mutations

Abdelkarim, Hazem; Leschinsky, Nicholas; Jang, Hyunbum; Banerjee, Avik; Nussinov, Ruth; Gaponenko, Vadim

doi:10.1016/j.sbi.2021.06.008

Cited by 12 publications

(6 citation statements)

References 56 publications

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“…It is of note that these D‐enriched proteins included calmodulin, calreticulin, and calumenin families, as well as NSC1, all of which are fundamental regulators of cellular Ca 2+ flux and oscillations [36–41]. Intriguingly, a calcium signaling pathway through the cAMP‐PKA axis is upstream of p‐CREB activation [42–44] and calmodulin activates MAPK signaling [38,45,46]. Taken together, this suggests that DARS inhibition downregulates calcium signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

Functional genomics screening identifies aspartyl‐tRNA synthetase as a novel prognostic marker and a therapeutic target for gastric cancers

Liu

Katoh

Komura

et al. 2022

The Journal of Pathology

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Efficient molecular targeting therapies for most gastric cancers (GCs) are currently lacking, despite GC being one of the most frequent and often devastating malignancies worldwide. Thus, identification of novel therapeutic targets for GC is in high demand. Recent advancements of high-throughput nucleic acid synthesis methods combined with next-generation sequencing (NGS) platforms have made it feasible to conduct functional genomics screening using large-scale pooled lentiviral libraries aimed at discovering novel cancer therapeutic targets. In this study, we performed NGS-based functional genomics screening for human GC cell lines using an originally constructed 6,399 shRNA library targeting all 2,096 human metabolism genes. Our screening identified aspartyl-tRNA synthetase (DARS) as a possible candidate for a therapeutic target for GC. In-house tissue microarrays containing 346 cases of GC combined with public datasets showed that patients with high expression levels of DARS protein exhibited more advanced clinicopathologic parameters and a worse prognosis, specifically among diffuse-type GC patients. Both in vitro and in vivo experiments concretely evidenced that DARS inhibition achieved robust growth suppression of GC cells. Moreover, RNA sequencing of GC cell lines under shRNA-mediated DARS knockdown suggested that DARS inhibition exerts its effect through the inactivation of multiple p-ERK pathways. This MAPK-related growth suppression by DARS inhibition would also be applicable to other cancers; thus, it is warranted to investigate the expression and clinical significance of DARS in a wide spectrum of malignancies. Taken together, NGS-based high-throughput pooled lentiviral screening showed DARS as a novel prognostic marker and a promising therapeutic target for GC.

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Section: Resultsmentioning

confidence: 99%

Functional genomics screening identifies aspartyl‐tRNA synthetase as a novel prognostic marker and a therapeutic target for gastric cancers

Liu

Katoh

Komura

et al. 2022

The Journal of Pathology

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“…We checked the reported crystal structure of calcium bound calbindin (6fie.pdb) 57 and it indicates these two hydrophobic amino acids in calbindin are in contact, and stabilized the closed state unlike the wild type calcium bound CaM. Wild type CaM is known to interact and regulate the activity of many proteins like p‐53, 5 Ras, 58 c‐Myc, 59 Bcl‐2, 60 which in turn affects cell signaling, 13 cell survival and cancer 61,62 . On the other hand, calbindin is mostly known to acts as buffer protein, carries calcium ion to different cytosolic compartment in the cell rather than interacting with other proteins significantly as CaM.…”

Section: Discussionmentioning

confidence: 99%

Energetic and structural insights behind calcium induced conformational transition in calmodulin

Halder,

Warshel

2023

Proteins

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Calmodulin (CaM) is a key signaling protein that triggers several cellular and physiological processes inside the cell. Upon binding with calcium ion, CaM undergoes large scale conformational transition from a closed state to an open state that facilitates its interaction with various target protein and regulates their activity. This work explores the origin of the energetic and structural variation of the wild type and mutated CaM and explores the molecular origin for the structural differences between them. We first calculated the sequential calcium binding energy to CaM using the PDLD/S‐LRA/β approach. This study shows a very good correlation with experimental calcium binding energies. Next we calculated the calcium binding energies to the wild type CaM and several mutated CaM systems which were reported experimentally. On the structural aspect, it has been reported experimentally that certain mutation (Q41L‐K75I) in calcium bound CaM leads to complete conformational transition from an open to a closed state. By using equilibrium molecular dynamics simulation, free energy calculation and contact frequency map analysis, we have shown that the formation of a cluster of long‐range hydrophobic contacts, initiated by the Q41L‐K75I CaM variant is the driving force behind its closing motion. This study unravels the energetics and structural aspects behind calcium ion induced conformational changes in wild type CaM and its variant.

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“…We surmised that these aberrant mutations might disrupt the kinase allosteric regulation, impairing molecular recognition and regulation with a concomitant impact on cell signalling. Previous studies have emphasized that perturbations of protein allosteric networks often arise from mutations [102,103]. With this in mind, we analysed the impact of point and in-frame fusion mutations on PKA-C allosteric cooperativity and seek for possible links to disease progression [19,48].…”

Section: Dysfunctional Allosteric Cooperativity In Cancer-driving Mut...mentioning

confidence: 99%

An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP‐dependent protein kinase A

et al. 2023

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The cAMP‐dependent protein kinase A (PKA) is the archetypical eukaryotic kinase. The catalytic subunit (PKA‐C) structure is highly conserved among the AGC‐kinase family. PKA‐C is a bilobal enzyme with a dynamic N‐lobe, harbouring the Adenosine‐5′‐triphosphate (ATP) binding site and a more rigid helical C‐lobe. The substrate‐binding groove resides at the interface of the two lobes. A distinct feature of PKA‐C is the positive binding cooperativity between nucleotide and substrate. Several PKA‐C mutations lead to the development of adenocarcinomas, myxomas, and other rare forms of liver tumours. Nuclear magnetic resonance (NMR) spectroscopy shows that these mutations disrupt the allosteric communication between the two lobes, causing a drastic decrease in binding cooperativity. The loss of cooperativity correlates with changes in substrate fidelity and reduced kinase affinity for the endogenous protein kinase inhibitor (PKI). The similarity between PKI and the inhibitory sequence of the kinase regulatory subunits suggests that the overall mechanism of regulation of the kinase may be disrupted. We surmise that a reduced or obliterated cooperativity may constitute a common trait for both orthosteric and allosteric mutations of PKA‐C that may lead to dysregulation and disease.

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The dynamic nature of the K-Ras/calmodulin complex can be altered by oncogenic mutations

Cited by 12 publications

References 56 publications

Functional genomics screening identifies aspartyl‐tRNA synthetase as a novel prognostic marker and a therapeutic target for gastric cancers

Functional genomics screening identifies aspartyl‐tRNA synthetase as a novel prognostic marker and a therapeutic target for gastric cancers

Energetic and structural insights behind calcium induced conformational transition in calmodulin

An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP‐dependent protein kinase A

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