Tuning the “violin” of protein kinases: The role of dynamics‐based allostery

Ahuja, Lalima G.; Taylor, Susan S.; Kornev, Alexandr P.

doi:10.1002/iub.2057

Cited by 60 publications

(51 citation statements)

References 85 publications

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“…Kinases are characterized by very complex conformational changes and several dynamic elements [100,101], we thus collected all-atom MD simulations in explicit solvent to provide the first description of the ensemble of conformations of the ULK1 kinase domain in solution. An ensemble of conformations as the one provided by MD is also useful in the structural analyses that we used for the annotation of the mutations found in ULK1 in cancer genomics study (see below), as we recently applied to other target proteins [48,102].…”

Section: Ulk1 Microsecond Dynamicsmentioning

confidence: 99%

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Kumar

Papaleo

2019

Preprint

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Autophagy is a key clearance process for the cell to recycle damaged cellular components. Autophagy is also well known for its dual role in cancer, acting as both tumor suppressor or promoter in a context-dependent way. One important upstream regulator of autophagy is the kinase ULK1. Several structures of the kinase domain of ULK1 have been solved, but a comprehensive study, including molecular dynamics, is currently missing. Also, an exhaustive description of the landscape of ULK1 cancer-related alterations is presently lacking. We here exploited the large amount of data on more than 30 cancer types through The Cancer Genome Atlas and the Recount2 initiatives to identify and analyze the atlas of ULK1 alterations in terms of gene expression and mutations. Moreover, we predicted the effects of mutations on ULK1 function and structural stability using a computational workflow accounting for protein dynamics and different layers of changes that a mutation can induce in a protein.We discovered that ULK1, along with ULK2 are down-regulated in gynecological tumors, suggesting an impairment of the upstream regulation of autophagy. In other cancer types, ULK2 can compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression level have been found for both genes. We identified 36 missense mutations of ULK1 especially in uterine, colon, stomach and lung cancer that were co-occurring with mutations in a large number of ULK1 interactors, suggesting a pronounced effect of the upstream steps of autophagy in these cancer types. Moreover, our study allowed to pinpoint that more than 50% of the mutations of ULK1 found in the cancer samples affect protein stability, which is likely to affect the cellular level and turnover of the protein. Among the damaging mutations for stability, A125T, F273V, L215P, F14L, and G12D are also predicted not to alter the functional state of the protein. Three mutations (S184F, D102N, and A28V) are predicted with the only impact on kinase activity, either modifying the functional dynamics of the protein or the capability to exert effects from distal site to the functional and catalytic regions. The framework here applied could be extended more broadly to other targets to help in the classification of mutational effects in disease, to prioritize variants for experimental validation or select the appropriate biological readouts for experiments.suggested to play essential scaffolding roles for autophagosome formation and maturation [9]. ULK1 has been reported overexpressed or downregulated in different cancer types or subtypes [25][26][27][28]. Autophagy in general has a strong association with cancer and can act with a dual role in a context-dependent way, being both tumor suppressor or promoter [29,30]. AMPK-ULK1 mediated autophagy also induces resistance against bromodomain and extraterminal domain inhibitors, which are novel epigenetic therapeutics for acute myeloid leukemia [31].So it can be a pivotal target to curb the chemotherapeutic resistance in cancers....

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Section: Ulk1 Microsecond Dynamicsmentioning

confidence: 99%

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Kumar

Papaleo

2019

Preprint

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“…On the other hand, a model developed from the work of Koshland, Nemethy and Filmer [27], known as "induced fit", asserts that the binding of an allosteric effector leads to a new, previously unpopulated conformation of the protein, with a modified binding activity at other sites [19,26]. While these conformation-based allostery models emphasized the thermodynamic states of the transforming proteins, Dryden and Cooper proposed that allostery can also involve changes in conformational dynamics [28,29]. There has been much interest in defining the potential role of dynamics in allosteric transitions and more generally, the dynamics of large-scale correlated motions of domains and subunits [30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Single-molecule FRET methods to study the dynamics of proteins at work

Mazal

Haran

2019

Current Opinion in Biomedical Engineering

110

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Feynman commented that "Everything that living things do can be understood in terms of the jiggling and wiggling of atoms". Proteins can jiggle and wiggle large structural elements such as domains and subunits as part of their functional cycles. Single-molecule fluorescence resonance energy transfer (smFRET) is an excellent tool to study conformational dynamics and decipher coordinated large-scale motions within proteins. smFRET methods introduced in recent years are geared toward understanding the time scales and amplitudes of function-related motions. This review discusses the methodology for obtaining and analyzing smFRET temporal trajectories that provide direct dynamic information on transitions between conformational states. It also introduces correlation methods that are useful for characterizing intramolecular motions. This arsenal of techniques has been used to study multiple molecular systems, from membrane proteins through molecular chaperones, and we examine some of these studies here. Recent exciting methodological novelties permit revealing very fast, submillisecond dynamics, whose relevance to protein function is yet to be fully grasped.

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“…cAMP is a highly conserved second messenger that is produced by adenylate cyclase in response to the stimulation of G protein-coupled receptors (GPCRs) by hormones or neutransmitters. The principal downstream effector of cAMP is protein kinase A (PKA; Ahuja et al, 2019). Localization of PKA at distinct intracellular compartments by A-Kinase Anchor Proteins (AKAPs) locally modulates key biological activities (Feliciello et al, 2001;Merrill and Strack, 2014;Rinaldi et al, 2016Rinaldi et al, , 2017Rinaldi et al, , 2018.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Homeostasis and Signaling in Parkinson’s Disease

Scorziello

Borzacchiello

Sisalli

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson's disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.

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Tuning the “violin” of protein kinases: The role of dynamics‐based allostery

Cited by 60 publications

References 85 publications

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Single-molecule FRET methods to study the dynamics of proteins at work

Mitochondrial Homeostasis and Signaling in Parkinson’s Disease

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