Hot topic: Crystal structure of LPA6, a receptor for lysophosphatidic acid, at 3.2A

Lysophospholipids (LPs) have myriad roles as extracellular signals that activate cognate G protein-coupled receptors (GPCRs) (2). LPs for which receptors have been reported include lysophosphatidic acid (LPA) (receptors: LPA1-6), sphingosine 1-phosphate (S1P1-5), lysophosphatidyl serine (LPS1-3, 2L (2L is a pseudogene in humans)) and lysophosphatidyl inositol/glucose (LPI/LPG), all of which are Class A GPCRs. Of these 15 LP receptors, crystal structures of two have been previously reported for S1P1 (2.8-3.35A) (3) and LPA1 (2.9-3.0A) (4) both of which utilized human cDNA sequences bound in the presence of antagonists. The new structure (1), from the laboratories of Junken Aoki and Osamu Nureki, elucidates a zebrafish receptor – with 80% amino acid similarity to human LPA6, in the transmembrane (TM) region – in the absence of a ligand, which nonetheless crystalized. This contrasts with the prior 2 antagonist-bound human structures. All 3 receptors were chimeric proteins stabilized by T4-lysozyme (S1P1 and LPA6) or thermostabilized apocytochrome b562RIL (LPA1) fused to the 3rd intracellular loop, but all were capable of responding to native ligands.

Key features of LPA6 included a surprisingly large distance between TM4 and 5, which suggests lateral entry of LPA via membrane translocation into the LPA6 binding pocket. Such a mechanism contrasts with that of LPA1 in which TM1 and 7 distances are comparatively small, and whose structure includes a barrel opening flexibly covered by an unstabilized N-terminal helix that contrasts with a stabilized helix in S1P1 that could inhibit ligand entry from extracellular space. LPA1’s structure is further consistent with LPA entry from the extracellular environment that could include its biosynthetic enzyme, autotaxin. By comparision, both S1P1 and LPA6 – despite being of distinct gene sub-families (EDG and P2Y, respectively) – show receptor entry of ligands from within the membrane plane, suggesting parallel evolution of membrane access for these gene sub-families. LPA6 prefers unsaturated LPAs (e.g., 18:2) that appear to enter a hydrophobic cleft and central cavity binding site that supports unsaturated LPA species based upon docking models. Modeling also supports LPA-binding that produces a shift of TM6 and 7 to allow more favorable interactions with LPA’s phosphate headgroup. Membrane access of LPA into LPA6 is further supported by actions of the phospholipase PA-PLA1α that was shown to increase membrane LPA without extracellular secretion, thus providing membrane ligand that could translocate into LPA6.

Comments by Jerold Chun, MD, PhD, Professor & Senior Vice President, Neuroscience Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

  1. Taniguchi, R. et al. (2017) Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6. Nature, 548, 356-360, doi:10.1038/nature23448. [PMID:28792932]
  2. Kihara, Y. et al. (2014) Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br J Pharmacol, 171, 3575-3594, doi:10.1111/bph.12678 . [PMID:24602016]
  3. Hanson, M. A. et al. (2012) Crystal structure of a lipid G protein-coupled receptor. Science, 335, 851-855, doi:10.1126/science.1215904 . [PMID:22344443]
  4. Chrencik, J. E. et al. (2015) Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1. Cell, 161, 1633-1643, doi:10.1016/j.cell.2015.06.002 . [PMID:26091040]
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