Dhirendra K Simanshu1, Xiuhong Zhai2, David Munch3, Daniel Hofius3, Jonathan E Markham4, Jacek Bielawski5, Alicja Bielawska5, Lucy Malinina6, Julian G Molotkovsky7, John W Mundy8, Dinshaw J Patel9, Rhoderick E Brown10. 1. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. 2. Hormel Institute, University of Minnesota, Austin, MN 55912, USA. 3. Department of Biology, BioCenter, University of Copenhagen, 2200 Copenhagen N, Denmark. 4. Department of Biochemistry, University of Nebraska, N146 Beadle Center, Lincoln, NE 68588, USA. 5. Department of Biochemistry and Molecular Biology, Lipidomics Shared Resource Mass Spectrometry Lab, Medical University of South Carolina, Charleston, SC 29425, USA. 6. Structural Biology Unit, CIC bioGUNE, Technology Park of Bizkaia, 48160 Derio-Bilbao, Spain. 7. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia. 8. Department of Biology, BioCenter, University of Copenhagen, 2200 Copenhagen N, Denmark. Electronic address: mundy@science.ku.dk. 9. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: pateld@mskcc.org. 10. Hormel Institute, University of Minnesota, Austin, MN 55912, USA. Electronic address: reb@umn.edu.
Abstract
The accelerated cell death 11 (acd11) mutant of Arabidopsis provides a genetic model for studying immune response activation and localized cellular suicide that halt pathogen spread during infection in plants. Here, we elucidate ACD11 structure and function and show that acd11 disruption dramatically alters the in vivo balance of sphingolipid mediators that regulate eukaryotic-programmed cell death. In acd11 mutants, normally low ceramide-1-phosphate (C1P) levels become elevated, but the relatively abundant cell death inducer phytoceramide rises acutely. ACD11 exhibits selective intermembrane transfer of C1P and phyto-C1P. Crystal structures establish C1P binding via a surface-localized, phosphate headgroup recognition center connected to an interior hydrophobic pocket that adaptively ensheaths lipid chains via a cleft-like gating mechanism. Point mutation mapping confirms functional involvement of binding site residues. A π helix (π bulge) near the lipid binding cleft distinguishes apo-ACD11 from other GLTP folds. The global two-layer, α-helically dominated, "sandwich" topology displaying C1P-selective binding identifies ACD11 as the plant prototype of a GLTP fold subfamily.
The accelerated cell death 11 (pan class="Gene">acd11) mutant of pan class="Species">Arabidopsis provides a genetic model for studying immune response activation and localized cellular suicide that halt pathogen spread during infection in plants. Here, we elucidate ACD11 structure and function and show that acd11 disruption dramatically alters the in vivo balance of sphingolipid mediators that regulate eukaryotic-programmed cell death. In acd11 mutants, normally low ceramide-1-phosphate (C1P) levels become elevated, but the relatively abundant cell death inducerphytoceramide rises acutely. ACD11 exhibits selective intermembrane transfer of C1P and phyto-C1P. Crystal structures establish C1P binding via a surface-localized, phosphate headgroup recognition center connected to an interior hydrophobic pocket that adaptively ensheaths lipid chains via a cleft-like gating mechanism. Point mutation mapping confirms functional involvement of binding site residues. A π helix (π bulge) near the lipid binding cleft distinguishes apo-ACD11 from other GLTP folds. The global two-layer, α-helically dominated, "sandwich" topology displaying C1P-selective binding identifies ACD11 as the plant prototype of a GLTP fold subfamily.
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