4A6K: Crystal Structure Of Slm1-Ph Domain In Complex With D-Myo-Inositol-4-Phosphate

BACKGROUND: 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 beta-strands 1 and 2: i) a canonical binding site delimited by the beta1-beta2 and beta3-beta4loops and ii) a non-canonical binding site bordered by the beta1-beta2 and beta5-beta6loops. 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. PRINCIPAL FINDINGS: 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 positively charged surface that contacts a phosphate group was identified next to the canonical binding site. CONCLUSIONS: Our results suggest that Slm1-PH utilizes a non-canonical binding site to bind PtdInsPs, similar to that described for the PH domains of beta-spectrin, Tiam1 and ArhGAP9. Additionally, Slm1-PH may have retained an active canonical site. We propose that the presence of both a canonical and a non-canonical binding pocket in Slm1-PH may account for the cooperative binding to PtdInsPs and DHS-1P.
PDB ID: 4A6KDownload
MMDB ID: 100488
PDB Deposition Date: 2011/11/4
Updated in MMDB: 2012/06
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Similar Structures:
Biological Unit for 4A6K: tetrameric; determined by author and by software (PISA)
Molecular Components in 4A6K
Label Count Molecule
Proteins (4 molecules)
Phosphatidylinositol 4,5-bisphosphate-binding PRO Slm1(Gene symbol: SLM1)
Molecule annotation
Chemicals (10 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB