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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [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

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.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-76SF00515; MH58570; 11POST6640005
OSTI ID:
1532484
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 22; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
English

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Cited By (1)

Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination journal May 2019