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Title: Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2

Abstract

Metazoan cell polarity is controlled by a set of highly conserved proteins. Lethal giant larvae (Lgl) functions in apical-basal polarity through phosphorylation-dependent interactions with several other proteins as well as the plasma membrane. Phosphorylation of Lgl by atypical protein kinase C (aPKC), a component of the partitioning-defective (Par) complex in epithelial cells, excludes Lgl from the apical membrane, a crucial step in the establishment of epithelial cell polarity. We present the crystal structures of human Lgl2 in both its unphosphorylated and aPKC-phosphorylated states. Lgl2 adopts a double β-propeller structure that is unchanged by aPKC phosphorylation of an unstructured loop in its second β-propeller, ruling out models of phosphorylation-dependent conformational change. Here, we demonstrate that phosphorylation controls the direct binding of purified Lgl2 to negative phospholipids in vitro. We also show that a coil–helix transition of this region that is promoted by phosphatidylinositol 4,5-bisphosphate (PIP 2) is also phosphorylation-dependent, implying a highly effective phosphorylative switch for membrane association.

Authors:
 [1];  [2];  [1];  [1];  [1]
  1. Stanford Univ., CA (United States). Dept. of Structural Biology; Stanford Univ., CA (United States). School of Medicine, Dept. of Molecular & Cellular Physiology
  2. Stanford Univ., CA (United States). Dept. of Structural Biology
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1532484
Grant/Contract Number:  
AC02-76SF00515; MH58570; 11POST6640005
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 22; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Lgl; cell polarity; aPKC

Citation Formats

Almagor, Lior, Ufimtsev, Ivan S., Ayer, Aruna, Li, Jingzhi, and Weis, William I. Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2. United States: N. p., 2019. Web. doi:10.1073/pnas.1821514116.
Almagor, Lior, Ufimtsev, Ivan S., Ayer, Aruna, Li, Jingzhi, & Weis, William I. Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2. United States. doi:10.1073/pnas.1821514116.
Almagor, Lior, Ufimtsev, Ivan S., Ayer, Aruna, Li, Jingzhi, and Weis, William I. Tue . "Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2". United States. doi:10.1073/pnas.1821514116.
@article{osti_1532484,
title = {Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2},
author = {Almagor, Lior and Ufimtsev, Ivan S. and Ayer, Aruna and Li, Jingzhi and Weis, William I.},
abstractNote = {Metazoan cell polarity is controlled by a set of highly conserved proteins. Lethal giant larvae (Lgl) functions in apical-basal polarity through phosphorylation-dependent interactions with several other proteins as well as the plasma membrane. Phosphorylation of Lgl by atypical protein kinase C (aPKC), a component of the partitioning-defective (Par) complex in epithelial cells, excludes Lgl from the apical membrane, a crucial step in the establishment of epithelial cell polarity. We present the crystal structures of human Lgl2 in both its unphosphorylated and aPKC-phosphorylated states. Lgl2 adopts a double β-propeller structure that is unchanged by aPKC phosphorylation of an unstructured loop in its second β-propeller, ruling out models of phosphorylation-dependent conformational change. Here, we demonstrate that phosphorylation controls the direct binding of purified Lgl2 to negative phospholipids in vitro. We also show that a coil–helix transition of this region that is promoted by phosphatidylinositol 4,5-bisphosphate (PIP2) is also phosphorylation-dependent, implying a highly effective phosphorylative switch for membrane association.},
doi = {10.1073/pnas.1821514116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 22,
volume = 116,
place = {United States},
year = {2019},
month = {5}
}

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