Structural analyses of the Slm1-PH domain demonstrate ligand binding in the non-canonical site.

PloS One
Kanchan AnandAnne-Claude Gavin

Abstract

Pleckstrin homology (PH) domains are common membrane-targeting modules and their best characterized ligands are a set of important signaling lipids that include phosphatidylinositol phosphates (PtdInsPs). PH domains recognize PtdInsPs through two distinct mechanisms that use different binding pockets on opposite sides of the β-strands 1 and 2: i) a canonical binding site delimited by the β1-β2 and β3-β4loops and ii) a non-canonical binding site bordered by the β1-β2 and β5-β6loops. The PH domain-containing protein Slm1 from budding yeast Saccharomyces cerevisiae is required for actin cytoskeleton polarization and cell growth. We recently reported that this PH domain binds PtdInsPs and phosphorylated sphingolipids in a cooperative manner. To study the structural basis for the Slm1-PH domain (Slm1-PH) specificity, we co-crystallized this domain with different soluble compounds that have structures analogous to anionic lipid head groups of reported Slm1 ligands: inositol 4-phosphate, which mimics phosphatidylinositol-4-phosphate (PtdIns(4)P), and phosphoserine as a surrogate for dihydrosphingosine 1-phosphate (DHS1-P). We found electron densities for the ligands within the so-called non-canonical binding site. An additional positi...Continue Reading

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Citations

Jul 9, 2013·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Monika JoshiErnesto J Fuentes
Feb 13, 2016·Molecular Biology of the Cell·Deike J OmnusChristopher J Stefan
Aug 25, 2015·Cell Reports·Ivana VonkovaAnne-Claude Gavin
Jun 14, 2016·Cellular Logistics·Neeladri Sekhar RoyJames M Gruschus
May 3, 2018·Acta Crystallographica. Section F, Structural Biology Communications·Imtiaz AliMatthias P Müller
Dec 16, 2016·The Biochemical Journal·Tao NiRobert J C Gilbert
Sep 18, 2020·Microbiology and Molecular Biology Reviews : MMBR·Carla E LanzeJames B Konopka

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Methods Mentioned

BETA
X-ray
nuclear magnetic resonance
isothermal titration calorimetry
co-crystallization

Software Mentioned

PROMALS3D
PHENIX
XDS
PHASER
PyMOL
LIGPLOT
PROCHECK
COOT

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