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Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.

Jiang Y, Benz TL, Long SB
Science 372 1215-1219 (2021)
Cited: 27 times
EuropePMC logo PMID: 34112694

Abstract

Hedgehog proteins govern crucial developmental steps in animals and drive certain human cancers. Before they can function as signaling molecules, Hedgehog precursor proteins must undergo amino-terminal palmitoylation by Hedgehog acyltransferase (HHAT). We present cryo-electron microscopy structures of human HHAT in complex with its palmitoyl-coenzyme A substrate and of a product complex with a palmitoylated Hedgehog peptide at resolutions of 2.7 and 3.2 angstroms, respectively. The structures reveal how HHAT overcomes the challenges of bringing together substrates that have different physiochemical properties from opposite sides of the endoplasmic reticulum membrane within a membrane-embedded active site for catalysis. These principles are relevant to related enzymes that catalyze the acylation of Wnt and of the appetite-stimulating hormone ghrelin. The structural and mechanistic insights may advance the development of inhibitors for cancer.

Reviews - 7mhy mentioned but not cited (2)

  1. Access and utilization of long chain fatty acyl-CoA by zDHHC protein acyltransferases. Puthenveetil R, Gómez-Navarro N, Banerjee A. Curr Opin Struct Biol 77 102463 (2022)
  2. A rising tide lifts all MBOATs: recent progress in structural and functional understanding of membrane bound O-acyltransferases. Pierce MR, Hougland JL. Front Physiol 14 1167873 (2023)

Articles - 7mhy mentioned but not cited (5)

  1. Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. Jiang Y, Benz TL, Long SB. Science 372 1215-1219 (2021)
  2. Structure, mechanism, and inhibition of Hedgehog acyltransferase. Coupland CE, Andrei SA, Ansell TB, Carrique L, Kumar P, Sefer L, Schwab RA, Byrne EFX, Pardon E, Steyaert J, Magee AI, Lanyon-Hogg T, Sansom MSP, Tate EW, Siebold C. Mol Cell 81 5025-5038.e10 (2021)
  3. Antibody-Antigen Binding Interface Analysis in the Big Data Era. Reis PBPS, Barletta GP, Gagliardi L, Fortuna S, Soler MA, Rocchia W. Front Mol Biosci 9 945808 (2022)
  4. Discovery of novel inhibitors of ghrelin O-acyltransferase enzyme: an in-silico approach. Hosseini FS, Ghassempour A, Amanlou M. Res Pharm Sci 17 540-557 (2022)
  5. Research Support, Non-U.S. Gov't Novel variant in HHAT as a cause of different sex development with partial gonadal dysgenesis associated with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs: Case report. Baz-Redón N, Soler-Colomer L, Fernández-Cancio M, Benito-Sanz S, Garrido M, Moliné T, Clemente M, Camats-Tarruella N, Yeste D. Front Endocrinol (Lausanne) 13 957969 (2022)


Reviews citing this publication (7)

  1. Update and nomenclature proposal for mammalian lysophospholipid acyltransferases, which create membrane phospholipid diversity. Valentine WJ, Yanagida K, Kawana H, Kono N, Noda NN, Aoki J, Shindou H. J Biol Chem 298 101470 (2022)
  2. Emerging roles of protein palmitoylation and its modifying enzymes in cancer cell signal transduction and cancer therapy. Liu Z, Xiao M, Mo Y, Wang H, Han Y, Zhao X, Yang X, Liu Z, Xu B. Int J Biol Sci 18 3447-3457 (2022)
  3. Hedgehog Autoprocessing: From Structural Mechanisms to Drug Discovery. Kandel N, Wang C. Front Mol Biosci 9 900560 (2022)
  4. Cellular and molecular mechanisms of Hedgehog signalling. Zhang Y, Beachy PA. Nat Rev Mol Cell Biol (2023)
  5. Proteome-wide analysis of protein lipidation using chemical probes: in-gel fluorescence visualization, identification and quantification of N-myristoylation, N- and S-acylation, O-cholesterylation, S-farnesylation and S-geranylgeranylation. Kallemeijn WW, Lanyon-Hogg T, Panyain N, Goya Grocin A, Ciepla P, Morales-Sanfrutos J, Tate EW. Nat Protoc 16 5083-5122 (2021)
  6. Sonic hedgehog signaling in craniofacial development. Xu J, Iyyanar PPR, Lan Y, Jiang R. Differentiation 133 60-76 (2023)
  7. The Inseparable Relationship Between Cholesterol and Hedgehog Signaling. Siebold C, Rohatgi R. Annu Rev Biochem 92 273-298 (2023)

Articles citing this publication (13)

  1. Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Liu Y, Qi X, Donnelly L, Elghobashi-Meinhardt N, Long T, Zhou RW, Sun Y, Wang B, Li X. Nature 607 816-822 (2022)
  2. Structure and mechanism of a eukaryotic ceramide synthase complex. Xie T, Fang Q, Zhang Z, Wang Y, Dong F, Gong X. EMBO J 42 e114889 (2023)
  3. The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3. Zhang Q, Yao D, Rao B, Jian L, Chen Y, Hu K, Xia Y, Li S, Shen Y, Qin A, Zhao J, Zhou L, Lei M, Jiang XC, Cao Y. Nat Commun 12 6869 (2021)
  4. A Direct in vitro Fatty Acylation Assay for Hedgehog Acyltransferase. Schonbrun AR, Resh MD. Bio Protoc 12 e4573 (2022)
  5. Cellular Uptake of a Fluorescent Ligand Reveals Ghrelin O-Acyltransferase Interacts with Extracellular Peptides and Exhibits Unexpected Localization for a Secretory Pathway Enzyme. Campaña MB, Davis TR, Novak SX, Cleverdon ER, Bates M, Krishnan N, Curtis ER, Childs MD, Pierce MR, Morales-Rodriguez Y, Sieburg MA, Hehnly H, Luyt LG, Hougland JL. ACS Chem Biol 18 1880-1890 (2023)
  6. Combined Computational-Biochemical Approach Offers an Accelerated Path to Membrane Protein Solubilization. Pierce MR, Ji J, Novak SX, Sieburg MA, Nangia S, Nangia S, Hougland JL. J Chem Inf Model 63 7159-7170 (2023)
  7. Gotta Go Slow: Two Evolutionarily Distinct Annelids Retain a Common Hedgehog Pathway Composition, Outlining Its Pan-Bilaterian Core. Platova S, Poliushkevich L, Kulakova M, Nesterenko M, Starunov V, Novikova E. Int J Mol Sci 23 14312 (2022)
  8. Hedgehog acyltransferase catalyzes a random sequential reaction and utilizes multiple fatty acyl-CoA substrates. Schonbrun AR, Resh MD. J Biol Chem 298 102422 (2022)
  9. Mechanism of D-alanine transfer to teichoic acids shows how bacteria acylate cell envelope polymers. Schultz BJ, Snow ED, Walker S. Nat Microbiol 8 1318-1329 (2023)
  10. Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis. Sui X, Wang K, Song K, Xu C, Song J, Lee CW, Liao M, Farese RV, Walther TC. Nat Commun 14 3100 (2023)
  11. Research Support, Non-U.S. Gov't Open Biology: overview for special issue on dynamics of protein fatty acylation. Resh MD. Open Biol 11 210228 (2021)
  12. Senescent renal tubular epithelial cells activate fibroblasts by secreting Shh to promote the progression of diabetic kidney disease. Wang D, Yin L, Chen R, Tan W, Liang L, Xiang J, Zhang H, Zhou X, Deng H, Guo B, Wang Y. Front Med (Lausanne) 9 1018298 (2022)
  13. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification. Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV. Nat Commun 14 3533 (2023)


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