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Molecular insights into the membrane-associated phosphatidylinositol 4-kinase II?.

ABSTRACT: Phosphatidylinositol 4-kinase II? (PI4KII?), a membrane-associated PI kinase, plays a central role in cell signalling and trafficking. Its kinase activity critically depends on palmitoylation of its cysteine-rich motif (-CCPCC-) and is modulated by the membrane environment. Lack of atomic structure impairs our understanding of the mechanism regulating kinase activity. Here we present the crystal structure of human PI4KII? in ADP-bound form. The structure identifies the nucleotide-binding pocket that differs notably from that found in PI3Ks. Two structural insertions, a palmitoylation insertion and an RK-rich insertion, endow PI4KII? with the 'integral' membrane-binding feature. Molecular dynamics simulations, biochemical and mutagenesis studies reveal that the palmitoylation insertion, containing an amphipathic helix, contributes to the PI-binding pocket and anchors PI4KII? to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KII?'s activity. We conclude from our results that PI4KII?'s activity is regulated indirectly through changes in the membrane environment.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC3974213 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα.

Zhou Qiangjun Q Li Jiangmei J Yu Hang H Zhai Yujia Y Gao Zhen Z Liu Yanxin Y Pang Xiaoyun X Zhang Lunfeng L Schulten Klaus K Sun Fei F Chen Chang C

Nature communications 20140328

Phosphatidylinositol 4-kinase IIα (PI4KIIα), a membrane-associated PI kinase, plays a central role in cell signalling and trafficking. Its kinase activity critically depends on palmitoylation of its cysteine-rich motif (-CCPCC-) and is modulated by the membrane environment. Lack of atomic structure impairs our understanding of the mechanism regulating kinase activity. Here we present the crystal structure of human PI4KIIα in ADP-bound form. The structure identifies the nucleotide-binding pocket ...[more]

PMID: 24675427

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Project description:Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a compensatory increase in insulin release, which has been shown to reduce the efficacy of treatment by reactivating the PI3K pathway in preclinical models. Patients with an absolute or relative deficiency in insulin, and those with insulin resistance or pancreatic dysfunction, may experience exacerbated or prolonged hyperglycemia. Therefore, the effective management of PI3Ki-associated hyperglycemia depends on early identification of patients at risk, frequent monitoring to allow prompt recognition of hyperglycemia and its sequelae, and initiating appropriate management strategies. Risk factors for the development of hyperglycemia include older age (≥75 years), overweight/obese at baseline, and family history of diabetes. Consultation with an endocrinologist is recommended for patients considered high risk. The management of PI3Ki-induced hyperglycemia requires an integrative approach that combines diets low in carbohydrates and glucose-lowering medications. Medications that do not affect the PI3K pathway are preferred as the primary and secondary agents for the management of hyperglycemia. These include metformin, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors. Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect of PI3K signaling. Clinical studies show that alpelisib-associated hyperglycemia is reversible and manageable, rarely leading to treatment discontinuation. Management of PI3Ki-associated hyperglycemia in patients with breast cancer should focus on the prevention of acute and subacute complications of hyperglycemia, allowing patients to remain on anticancer treatment longer.

Dataset Information

Molecular insights into the membrane-associated phosphatidylinositol 4-kinase II?.

Publications

Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα.

Similar Datasets

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