دورية أكاديمية
Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site engineering of sphingomyelin synthases.
| العنوان: | Switching head group selectivity in mammalian sphingolipid biosynthesis by active-site engineering of sphingomyelin synthases. |
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| المؤلفون: | Kol M; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany Membrane Biochemistry & Biophysics, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands., Panatala R; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany Membrane Biochemistry & Biophysics, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands., Nordmann M; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany., Swart L; Membrane Biochemistry & Biophysics, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands., van Suijlekom L; Membrane Biochemistry & Biophysics, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands., Cabukusta B; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany., Hilderink A; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany., Grabietz T; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany., Mina JG; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany., Somerharju P; Medical Biochemistry, Institute of Biomedicine, University of Helsinki, Helsinki 00014, Finland., Korneev S; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany., Tafesse FG; Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239., Holthuis JC; Molecular Cell Biology Division, Department of Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany Membrane Biochemistry & Biophysics, Bijvoet Center and Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, The Netherlands holthuis@uos.de. |
| المصدر: | Journal of lipid research [J Lipid Res] 2016 Jul; Vol. 57 (7), pp. 1273-85. Date of Electronic Publication: 2016 May 10. |
| نوع المنشور: | Journal Article; Retracted Publication |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: Memphis, Lipid Research, inc. |
| مواضيع طبية MeSH: | Protein Engineering*, Membrane Proteins/*genetics , Nerve Tissue Proteins/*genetics , Sphingomyelins/*biosynthesis , Transferases (Other Substituted Phosphate Groups)/*genetics, Cell Membrane/enzymology ; Cell Membrane/metabolism ; Cell-Free System ; Click Chemistry ; Endoplasmic Reticulum/enzymology ; Golgi Apparatus/enzymology ; HeLa Cells ; Humans ; Membrane Proteins/chemistry ; Mutagenesis, Site-Directed ; Nerve Tissue Proteins/chemistry ; Sphingomyelins/genetics ; Transferases (Other Substituted Phosphate Groups)/chemistry |
| مستخلص: | SM is a fundamental component of mammalian cell membranes that contributes to mechanical stability, signaling, and sorting. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase (SMS) 1 in the Golgi and SMS2 at the plasma membrane. Mammalian cells also synthesize trace amounts of the SM analog ceramide phosphoethanolamine (CPE), but the physiological relevance of CPE production is unclear. Previous work revealed that SMS2 is a bifunctional enzyme producing both SM and CPE, whereas a closely related enzyme, sphingomyelin synthase-related protein (SMSr)/SAMD8, acts as a monofunctional CPE synthase in the endoplasmatic reticulum. Using domain swapping and site-directed mutagenesis on enzymes expressed in defined lipid environments, we here identified structural determinants that mediate head group selectivity of SMS family members. Notably, a single residue adjacent to the catalytic histidine in the third exoplasmic loop profoundly influenced enzyme specificity, with glutamic acid permitting SMS-catalyzed CPE production and aspartic acid confining the enzyme to produce SM. An exchange of exoplasmic residues with SMSr proved sufficient to convert SMS1 into a bulk CPE synthase. This allowed us to establish mammalian cells that produce CPE rather than SM as the principal phosphosphingolipid and provide a model of the molecular interactions that impart catalytic specificity among SMS enzymes. (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.) |
| التعليقات: | Retraction in: J Lipid Res. 2017 Apr;58(4):821. (PMID: 28365668) |
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| فهرسة مساهمة: | Keywords: Golgi apparatus; cell-free expression; ceramide phosphoethanolamine; click chemistry; enzyme mechanisms; lipid biochemistry; lipidomics; model membranes; protein engineering |
| المشرفين على المادة: | 0 (Membrane Proteins) 0 (Nerve Tissue Proteins) 0 (Sphingomyelins) 112130-78-6 (ceramide phosphoethanolamine) EC 2.7.8.- (SAMD8 protein, human) EC 2.7.8.- (SGMS1 protein, human) EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups)) |
| تواريخ الأحداث: | Date Created: 20160512 Date Completed: 20170824 Latest Revision: 20210217 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC4918856 |
| DOI: | 10.1194/jlr.M068692 |
| PMID: | 27165857 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1539-7262 |
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| DOI: | 10.1194/jlr.M068692 |