4a6f

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Crystal structure of Slm1-PH domain in complex with Phosphoserine

Structural highlights

4a6f is a 2 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.68Å
Ligands:PO4, SEP
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SLM1_YEAST Together with SLM2, effector of the TORC2- and calcineurin-signaling pathways. Phosphorylated and activated by TORC2 under favorable growth conditions. Mediates actin polarization via inhibition of calcineurin-dependent transcription. Upon nutrient limitation or environmental stress, gets dephosphorylated by calcineurin. Dephosphorylation inhibits its interaction with TORC2, thereby antagonizing TORC2 signaling and mediating calcineurin-dependent actin depolarization. Also functions in heat-induced, calcineurin-mediated uracil permease (FUR4) endocytosis.[1] [2] [3] [4]

Publication Abstract from PubMed

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.

Structural Analyses of the Slm1-PH Domain Demonstrate Ligand Binding in the Non-Canonical Site.,Anand K, Maeda K, Gavin AC PLoS One. 2012;7(5):e36526. Epub 2012 May 4. PMID:22574179[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. Audhya A, Loewith R, Parsons AB, Gao L, Tabuchi M, Zhou H, Boone C, Hall MN, Emr SD. Genome-wide lethality screen identifies new PI4,5P2 effectors that regulate the actin cytoskeleton. EMBO J. 2004 Oct 1;23(19):3747-57. Epub 2004 Sep 16. PMID:15372071 doi:10.1038/sj.emboj.7600384
  2. Fadri M, Daquinag A, Wang S, Xue T, Kunz J. The pleckstrin homology domain proteins Slm1 and Slm2 are required for actin cytoskeleton organization in yeast and bind phosphatidylinositol-4,5-bisphosphate and TORC2. Mol Biol Cell. 2005 Apr;16(4):1883-900. Epub 2005 Feb 2. PMID:15689497 doi:E04-07-0564
  3. Mulet JM, Martin DE, Loewith R, Hall MN. Mutual antagonism of target of rapamycin and calcineurin signaling. J Biol Chem. 2006 Nov 3;281(44):33000-7. Epub 2006 Sep 7. PMID:16959779 doi:M604244200
  4. Bultynck G, Heath VL, Majeed AP, Galan JM, Haguenauer-Tsapis R, Cyert MS. Slm1 and slm2 are novel substrates of the calcineurin phosphatase required for heat stress-induced endocytosis of the yeast uracil permease. Mol Cell Biol. 2006 Jun;26(12):4729-45. PMID:16738335 doi:10.1128/MCB.01973-05
  5. Anand K, Maeda K, Gavin AC. Structural Analyses of the Slm1-PH Domain Demonstrate Ligand Binding in the Non-Canonical Site. PLoS One. 2012;7(5):e36526. Epub 2012 May 4. PMID:22574179 doi:10.1371/journal.pone.0036526

Contents


PDB ID 4a6f

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