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

Almagor, Lior; Ufimtsev, Ivan S.; Ayer, Aruna; Li, Jingzhi; Weis, William I.

doi:10.1073/pnas.1821514116

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

Journal Article · 14 May 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1821514116 · OSTI ID:1532484

Almagor, Lior ^[1]; Ufimtsev, Ivan S. ^[2]; Ayer, Aruna ^[1]; Li, Jingzhi ^[1]; Weis, William I. ^[1]

Stanford Univ., CA (United States). Dept. of Structural Biology; Stanford Univ., CA (United States). School of Medicine, Dept. of Molecular & Cellular Physiology
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.

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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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Solving the structure of Lgl2, a difficult blind test of unsupervised structure determination Ufimtsev, Ivan S.; Almagor, Lior; Weis, William I. Proceedings of the National Academy of Sciences, Vol. 116, Issue 22 https://doi.org/10.1073/pnas.1821513116	journal	May 2019

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60 APPLIED LIFE SCIENCES
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Lgl
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Title: Structural insights into the aPKC regulatory switch mechanism of the human cell polarity protein lethal giant larvae 2

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