Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex
Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with pr...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2018-10, Vol.362 (6410) |
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| creator | Qi, Xiaofeng Schmiege, Philip Coutavas, Elias Li, Xiaochun |
| description | Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells. |
| doi_str_mv | 10.1126/science.aas8843 |
| format | Article |
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N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aas8843</identifier><identifier>PMID: 30139912</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Assaying ; Asymmetry ; Binders ; Binding sites ; Birth ; Birth defects ; Blocking ; Calcium (extracellular) ; Calcium - chemistry ; Calcium - physiology ; Calcium chloride ; Calcium ions ; Calcium-binding protein ; Cancer ; Cholesterol ; Congenital defects ; Cryoelectron Microscopy ; Electron microscopy ; Epitopes ; Hedgehog protein ; Hedgehog Proteins - chemistry ; Hedgehog Proteins - genetics ; Hedgehog Proteins - ultrastructure ; Humans ; Insertion ; Interfaces ; Microscopy ; Multiprotein Complexes - chemistry ; Multiprotein Complexes - genetics ; Multiprotein Complexes - ultrastructure ; Mutation ; Palmitic acid ; Palmitic Acid - chemistry ; Patched protein ; Patched-1 Receptor - chemistry ; Patched-1 Receptor - genetics ; Patched-1 Receptor - ultrastructure ; Physiology ; Protein Domains ; Proteins ; Receptors ; Signal Transduction ; Signaling ; Structural analysis ; Structural Analysis (Linguistics) ; Structural Analysis (Science)</subject><ispartof>Science (American Association for the Advancement of Science), 2018-10, Vol.362 (6410)</ispartof><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-3411798240e5a13f211d66f23c8b4b3c83ddecac6cdfd04a4c41cbd0fb9c6b263</citedby><cites>FETCH-LOGICAL-c487t-3411798240e5a13f211d66f23c8b4b3c83ddecac6cdfd04a4c41cbd0fb9c6b263</cites><orcidid>0000-0001-5703-7806 ; 0000-0001-8123-9627 ; 0000-0003-4904-0081 ; 0000-0002-0177-0803</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,2884,2885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30139912$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Qi, Xiaofeng</creatorcontrib><creatorcontrib>Schmiege, Philip</creatorcontrib><creatorcontrib>Coutavas, Elias</creatorcontrib><creatorcontrib>Li, Xiaochun</creatorcontrib><title>Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.</description><subject>Assaying</subject><subject>Asymmetry</subject><subject>Binders</subject><subject>Binding sites</subject><subject>Birth</subject><subject>Birth defects</subject><subject>Blocking</subject><subject>Calcium (extracellular)</subject><subject>Calcium - chemistry</subject><subject>Calcium - physiology</subject><subject>Calcium chloride</subject><subject>Calcium ions</subject><subject>Calcium-binding protein</subject><subject>Cancer</subject><subject>Cholesterol</subject><subject>Congenital defects</subject><subject>Cryoelectron Microscopy</subject><subject>Electron microscopy</subject><subject>Epitopes</subject><subject>Hedgehog protein</subject><subject>Hedgehog Proteins - chemistry</subject><subject>Hedgehog Proteins - genetics</subject><subject>Hedgehog Proteins - ultrastructure</subject><subject>Humans</subject><subject>Insertion</subject><subject>Interfaces</subject><subject>Microscopy</subject><subject>Multiprotein Complexes - chemistry</subject><subject>Multiprotein Complexes - genetics</subject><subject>Multiprotein Complexes - ultrastructure</subject><subject>Mutation</subject><subject>Palmitic acid</subject><subject>Palmitic Acid - chemistry</subject><subject>Patched protein</subject><subject>Patched-1 Receptor - chemistry</subject><subject>Patched-1 Receptor - genetics</subject><subject>Patched-1 Receptor - ultrastructure</subject><subject>Physiology</subject><subject>Protein Domains</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Structural analysis</subject><subject>Structural Analysis (Linguistics)</subject><subject>Structural Analysis (Science)</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkcFvFSEQxonR2Gf17M2QePGyLbPweMvFxDRqTZrooV4l7DC7j4aF57Kr9r-Xps9GvcCE78c3Ax9jL0GcAbT6vGCghHTmXOk6JR-xDQizbUwr5GO2EULqphO77Ql7VsqNEFUz8ik7kQKkMdBu2Lfrn5l_cQvuyfMpR8I1UuGURjcS96EsIeHCS1jqaU78kvxI-zzy20DRhzRyV8UxuVjrBvN0oIXSwu-qSL-esyeDi4VeHPdT9vXD--uLy-bq88dPF--uGlTdbmmkAtiZrlWCtg7k0AJ4rYdWYtervq7Se0KHGv3ghXIKFWDvxdAb1H2r5Sl7e-97WPuJPNYRZhftYQ6Tm29tdsH-q6Swt2P-YXVtrQxUgzdHgzl_X6ksdgoFKUaXKK_FtsJIKbQW24q-_g-9yetcf6BSAFop6MyuUuf3FM65lJmGh2FA2Lvs7DE7e8yu3nj19xse-D9hyd8Axpnf</recordid><startdate>20181005</startdate><enddate>20181005</enddate><creator>Qi, Xiaofeng</creator><creator>Schmiege, Philip</creator><creator>Coutavas, Elias</creator><creator>Li, Xiaochun</creator><general>The American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5703-7806</orcidid><orcidid>https://orcid.org/0000-0001-8123-9627</orcidid><orcidid>https://orcid.org/0000-0003-4904-0081</orcidid><orcidid>https://orcid.org/0000-0002-0177-0803</orcidid></search><sort><creationdate>20181005</creationdate><title>Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex</title><author>Qi, Xiaofeng ; Schmiege, Philip ; Coutavas, Elias ; Li, Xiaochun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-3411798240e5a13f211d66f23c8b4b3c83ddecac6cdfd04a4c41cbd0fb9c6b263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Assaying</topic><topic>Asymmetry</topic><topic>Binders</topic><topic>Binding sites</topic><topic>Birth</topic><topic>Birth defects</topic><topic>Blocking</topic><topic>Calcium (extracellular)</topic><topic>Calcium - chemistry</topic><topic>Calcium - physiology</topic><topic>Calcium chloride</topic><topic>Calcium ions</topic><topic>Calcium-binding protein</topic><topic>Cancer</topic><topic>Cholesterol</topic><topic>Congenital defects</topic><topic>Cryoelectron Microscopy</topic><topic>Electron microscopy</topic><topic>Epitopes</topic><topic>Hedgehog protein</topic><topic>Hedgehog Proteins - chemistry</topic><topic>Hedgehog Proteins - genetics</topic><topic>Hedgehog Proteins - ultrastructure</topic><topic>Humans</topic><topic>Insertion</topic><topic>Interfaces</topic><topic>Microscopy</topic><topic>Multiprotein Complexes - chemistry</topic><topic>Multiprotein Complexes - genetics</topic><topic>Multiprotein Complexes - ultrastructure</topic><topic>Mutation</topic><topic>Palmitic acid</topic><topic>Palmitic Acid - chemistry</topic><topic>Patched protein</topic><topic>Patched-1 Receptor - chemistry</topic><topic>Patched-1 Receptor - genetics</topic><topic>Patched-1 Receptor - ultrastructure</topic><topic>Physiology</topic><topic>Protein Domains</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Structural analysis</topic><topic>Structural Analysis (Linguistics)</topic><topic>Structural Analysis (Science)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Qi, Xiaofeng</creatorcontrib><creatorcontrib>Schmiege, Philip</creatorcontrib><creatorcontrib>Coutavas, Elias</creatorcontrib><creatorcontrib>Li, Xiaochun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Qi, Xiaofeng</au><au>Schmiege, Philip</au><au>Coutavas, Elias</au><au>Li, Xiaochun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2018-10-05</date><risdate>2018</risdate><volume>362</volume><issue>6410</issue><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>30139912</pmid><doi>10.1126/science.aas8843</doi><orcidid>https://orcid.org/0000-0001-5703-7806</orcidid><orcidid>https://orcid.org/0000-0001-8123-9627</orcidid><orcidid>https://orcid.org/0000-0003-4904-0081</orcidid><orcidid>https://orcid.org/0000-0002-0177-0803</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Assaying Asymmetry Binders Binding sites Birth Birth defects Blocking Calcium (extracellular) Calcium - chemistry Calcium - physiology Calcium chloride Calcium ions Calcium-binding protein Cancer Cholesterol Congenital defects Cryoelectron Microscopy Electron microscopy Epitopes Hedgehog protein Hedgehog Proteins - chemistry Hedgehog Proteins - genetics Hedgehog Proteins - ultrastructure Humans Insertion Interfaces Microscopy Multiprotein Complexes - chemistry Multiprotein Complexes - genetics Multiprotein Complexes - ultrastructure Mutation Palmitic acid Palmitic Acid - chemistry Patched protein Patched-1 Receptor - chemistry Patched-1 Receptor - genetics Patched-1 Receptor - ultrastructure Physiology Protein Domains Proteins Receptors Signal Transduction Signaling Structural analysis Structural Analysis (Linguistics) Structural Analysis (Science) |
| title | Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex |
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