A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL
Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in a variety of human tumor cell lines but not in normal cells [Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith,...
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| Veröffentlicht in: | Biochemistry (Easton) 2000-02, Vol.39 (4), p.633-640 |
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| creator | Hymowitz, Sarah G O'Connell, Mark P Ultsch, Mark H Hurst, Amy Totpal, Klara Ashkenazi, Avi de Vos, Abraham M Kelley, Robert F |
| description | Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in a variety of human tumor cell lines but not in normal cells [Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Immunity 3, 673−682; Pitti, R. M., Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., and Ashkenazi, A. (1996) J. Biol. Chem. 271, 12687−12690]. Here we describe the structure of Apo2L at 1.3 Å resolution and use alanine-scanning mutagenesis to map the receptor contact regions. The structure reveals a homotrimeric protein that resembles TNF with receptor-binding epitopes at the interface between monomers. A zinc ion is buried at the trimer interface, coordinated by the single cysteine residue of each monomer. The zinc ion is required for maintaining the native structure and stability and, hence, the biological activity of Apo2L. This is the first example of metal-dependent oligomerization and function of a cytokine. |
| doi_str_mv | 10.1021/bi992242l |
| format | Article |
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R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Immunity 3, 673−682; Pitti, R. M., Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., and Ashkenazi, A. (1996) J. Biol. Chem. 271, 12687−12690]. Here we describe the structure of Apo2L at 1.3 Å resolution and use alanine-scanning mutagenesis to map the receptor contact regions. The structure reveals a homotrimeric protein that resembles TNF with receptor-binding epitopes at the interface between monomers. A zinc ion is buried at the trimer interface, coordinated by the single cysteine residue of each monomer. The zinc ion is required for maintaining the native structure and stability and, hence, the biological activity of Apo2L. This is the first example of metal-dependent oligomerization and function of a cytokine.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi992242l</identifier><identifier>PMID: 10651627</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alanine - genetics ; Amino Acid Sequence ; Apoptosis ; Apoptosis Regulatory Proteins ; Binding Sites ; Circular Dichroism ; Crystallography, X-Ray ; DNA Mutational Analysis ; Humans ; Ligands ; Membrane Glycoproteins - chemistry ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Spectrometry, Fluorescence ; Structure-Activity Relationship ; TNF-Related Apoptosis-Inducing Ligand ; Tumor Necrosis Factor-alpha - chemistry ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism ; Zinc - chemistry ; Zinc - metabolism</subject><ispartof>Biochemistry (Easton), 2000-02, Vol.39 (4), p.633-640</ispartof><rights>Copyright © 2000 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a415t-d83c9f84b7c7fc08235cb4043998955d58f3fe605b479d2314f3e80beb2dda373</citedby><cites>FETCH-LOGICAL-a415t-d83c9f84b7c7fc08235cb4043998955d58f3fe605b479d2314f3e80beb2dda373</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/bi992242l$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bi992242l$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10651627$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hymowitz, Sarah G</creatorcontrib><creatorcontrib>O'Connell, Mark P</creatorcontrib><creatorcontrib>Ultsch, Mark H</creatorcontrib><creatorcontrib>Hurst, Amy</creatorcontrib><creatorcontrib>Totpal, Klara</creatorcontrib><creatorcontrib>Ashkenazi, Avi</creatorcontrib><creatorcontrib>de Vos, Abraham M</creatorcontrib><creatorcontrib>Kelley, Robert F</creatorcontrib><title>A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in a variety of human tumor cell lines but not in normal cells [Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Immunity 3, 673−682; Pitti, R. M., Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., and Ashkenazi, A. (1996) J. Biol. Chem. 271, 12687−12690]. Here we describe the structure of Apo2L at 1.3 Å resolution and use alanine-scanning mutagenesis to map the receptor contact regions. The structure reveals a homotrimeric protein that resembles TNF with receptor-binding epitopes at the interface between monomers. A zinc ion is buried at the trimer interface, coordinated by the single cysteine residue of each monomer. The zinc ion is required for maintaining the native structure and stability and, hence, the biological activity of Apo2L. This is the first example of metal-dependent oligomerization and function of a cytokine.</description><subject>Alanine - genetics</subject><subject>Amino Acid Sequence</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins</subject><subject>Binding Sites</subject><subject>Circular Dichroism</subject><subject>Crystallography, X-Ray</subject><subject>DNA Mutational Analysis</subject><subject>Humans</subject><subject>Ligands</subject><subject>Membrane Glycoproteins - chemistry</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutagenesis, Site-Directed</subject><subject>Spectrometry, Fluorescence</subject><subject>Structure-Activity Relationship</subject><subject>TNF-Related Apoptosis-Inducing Ligand</subject><subject>Tumor Necrosis Factor-alpha - chemistry</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Zinc - chemistry</subject><subject>Zinc - metabolism</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0LtOwzAUBmALgWgpDLwA8sLAYOprEo-lAlpRcelFQiyWYzvF0CbFSRB9e4KCKgYm68ifzuUH4JTgS4Ip6adeSko5Xe2BLhEUIy6l2AddjHGEqIxwBxyV5VtTchzzQ9AhOBIkonEX2AFc5P6jdvDF5wZd-dz6fAlnvnJw6j6dXjkL0y3UcOSXr2jqymJVV77I4TMKegtnVahNVQcHiwyOinVRBb92wRs42BR00p9PB-PJMTjI9Kp0J79vDyxurufDEZo83I6HgwnSnIgK2YQZmSU8jU2cGZxQJkzKMWdSJlIIK5KMZS7CIuWxtJQRnjGX4NSl1FrNYtYDF21fE4qyDC5Tm2YbHbaKYPWTlNol1diz1m7qdO3sH9lG0wDUAl9W7mv3r8O7imIWCzV_nKkRT-aC3D2p-8aft16bUr0VdcibU_8Z_A1_Jn1n</recordid><startdate>20000201</startdate><enddate>20000201</enddate><creator>Hymowitz, Sarah G</creator><creator>O'Connell, Mark P</creator><creator>Ultsch, Mark H</creator><creator>Hurst, Amy</creator><creator>Totpal, Klara</creator><creator>Ashkenazi, Avi</creator><creator>de Vos, Abraham M</creator><creator>Kelley, Robert F</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20000201</creationdate><title>A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL</title><author>Hymowitz, Sarah G ; O'Connell, Mark P ; Ultsch, Mark H ; Hurst, Amy ; Totpal, Klara ; Ashkenazi, Avi ; de Vos, Abraham M ; Kelley, Robert F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a415t-d83c9f84b7c7fc08235cb4043998955d58f3fe605b479d2314f3e80beb2dda373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Alanine - genetics</topic><topic>Amino Acid Sequence</topic><topic>Apoptosis</topic><topic>Apoptosis Regulatory Proteins</topic><topic>Binding Sites</topic><topic>Circular Dichroism</topic><topic>Crystallography, X-Ray</topic><topic>DNA Mutational Analysis</topic><topic>Humans</topic><topic>Ligands</topic><topic>Membrane Glycoproteins - chemistry</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutagenesis, Site-Directed</topic><topic>Spectrometry, Fluorescence</topic><topic>Structure-Activity Relationship</topic><topic>TNF-Related Apoptosis-Inducing Ligand</topic><topic>Tumor Necrosis Factor-alpha - chemistry</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Zinc - chemistry</topic><topic>Zinc - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hymowitz, Sarah G</creatorcontrib><creatorcontrib>O'Connell, Mark P</creatorcontrib><creatorcontrib>Ultsch, Mark H</creatorcontrib><creatorcontrib>Hurst, Amy</creatorcontrib><creatorcontrib>Totpal, Klara</creatorcontrib><creatorcontrib>Ashkenazi, Avi</creatorcontrib><creatorcontrib>de Vos, Abraham M</creatorcontrib><creatorcontrib>Kelley, Robert F</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hymowitz, Sarah G</au><au>O'Connell, Mark P</au><au>Ultsch, Mark H</au><au>Hurst, Amy</au><au>Totpal, Klara</au><au>Ashkenazi, Avi</au><au>de Vos, Abraham M</au><au>Kelley, Robert F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2000-02-01</date><risdate>2000</risdate><volume>39</volume><issue>4</issue><spage>633</spage><epage>640</epage><pages>633-640</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>Apoptosis-inducing ligand 2 (Apo2L, also called TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in a variety of human tumor cell lines but not in normal cells [Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C.-P., Nicholl, J. K., Sutherland, G. R., Smith, T. D., Rauch, C., Smith, C. A., and Goodwin, R. G. (1995) Immunity 3, 673−682; Pitti, R. M., Marsters, S. A., Ruppert, S., Donahue, C. J., Moore, A., and Ashkenazi, A. (1996) J. Biol. Chem. 271, 12687−12690]. Here we describe the structure of Apo2L at 1.3 Å resolution and use alanine-scanning mutagenesis to map the receptor contact regions. The structure reveals a homotrimeric protein that resembles TNF with receptor-binding epitopes at the interface between monomers. A zinc ion is buried at the trimer interface, coordinated by the single cysteine residue of each monomer. The zinc ion is required for maintaining the native structure and stability and, hence, the biological activity of Apo2L. This is the first example of metal-dependent oligomerization and function of a cytokine.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>10651627</pmid><doi>10.1021/bi992242l</doi><tpages>8</tpages></addata></record> |
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| subjects | Alanine - genetics Amino Acid Sequence Apoptosis Apoptosis Regulatory Proteins Binding Sites Circular Dichroism Crystallography, X-Ray DNA Mutational Analysis Humans Ligands Membrane Glycoproteins - chemistry Membrane Glycoproteins - genetics Membrane Glycoproteins - metabolism Models, Molecular Molecular Sequence Data Mutagenesis, Site-Directed Spectrometry, Fluorescence Structure-Activity Relationship TNF-Related Apoptosis-Inducing Ligand Tumor Necrosis Factor-alpha - chemistry Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism Zinc - chemistry Zinc - metabolism |
| title | A Unique Zinc-Binding Site Revealed by a High-Resolution X-ray Structure of Homotrimeric Apo2L/TRAIL |
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