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

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

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...

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Main Authors: Zhou, Qiangjun, Li, Jiangmei, Yu, Hang, Zhai, Yujia, Gao, Zhen, Liu, Yanxin, Pang, Xiaoyun, Zhang, Lunfeng, Schulten, Klaus, Sun, Fei, Chen, Chang
Format: Online
Language:English
Published: Nature Pub. Group 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974213/
id pubmed-3974213
recordtype oai_dc
spelling pubmed-39742132014-04-04 Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα Zhou, Qiangjun Li, Jiangmei Yu, Hang Zhai, Yujia Gao, Zhen Liu, Yanxin Pang, Xiaoyun Zhang, Lunfeng Schulten, Klaus Sun, Fei Chen, Chang Article 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 that differs notably from that found in PI3Ks. Two structural insertions, a palmitoylation insertion and an RK-rich insertion, endow PI4KIIα 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 PI4KIIα to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KIIα’s activity. We conclude from our results that PI4KIIα’s activity is regulated indirectly through changes in the membrane environment. Nature Pub. Group 2014-03-28 /pmc/articles/PMC3974213/ /pubmed/24675427 http://dx.doi.org/10.1038/ncomms4552 Text en Copyright © 2014, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Zhou, Qiangjun
Li, Jiangmei
Yu, Hang
Zhai, Yujia
Gao, Zhen
Liu, Yanxin
Pang, Xiaoyun
Zhang, Lunfeng
Schulten, Klaus
Sun, Fei
Chen, Chang
spellingShingle Zhou, Qiangjun
Li, Jiangmei
Yu, Hang
Zhai, Yujia
Gao, Zhen
Liu, Yanxin
Pang, Xiaoyun
Zhang, Lunfeng
Schulten, Klaus
Sun, Fei
Chen, Chang
Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
author_facet Zhou, Qiangjun
Li, Jiangmei
Yu, Hang
Zhai, Yujia
Gao, Zhen
Liu, Yanxin
Pang, Xiaoyun
Zhang, Lunfeng
Schulten, Klaus
Sun, Fei
Chen, Chang
author_sort Zhou, Qiangjun
title Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
title_short Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
title_full Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
title_fullStr Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
title_full_unstemmed Molecular insights into the membrane-associated phosphatidylinositol 4-kinase IIα
title_sort molecular insights into the membrane-associated phosphatidylinositol 4-kinase iiα
description 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 that differs notably from that found in PI3Ks. Two structural insertions, a palmitoylation insertion and an RK-rich insertion, endow PI4KIIα 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 PI4KIIα to the membrane, suggesting that fluctuation of the palmitoylation insertion affects PI4KIIα’s activity. We conclude from our results that PI4KIIα’s activity is regulated indirectly through changes in the membrane environment.
publisher Nature Pub. Group
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974213/
_version_ 1612073704473231360

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