Ahmed-Noor A. Agip, J. N. Blaza, H. R. Bridges, C. Viscomi, S. Rawson, S. Muench, J. Hirst
Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recent cryo-EM analyses have produced near-complete models of all 45 subunits in the bovine, ovine and porcine complexes and have identified two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-A structure of complex I from mouse heart mitochondria, a biomedically relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside kinase homolog, and define mechanistically critical elements in the mammalian enzyme. By comparisons with a 3.9-A structure of the 'deactive' state and with known bacterial structures, we identify differences in helical geometry in the membrane domain that occur upon activation or that alter the positions of catalytically important charged residues. Our results demonstrate the capability of cryo-EM analyses to challenge and develop mechanistic models for mammalian complex I.
{"title":"Mouse mitochondrial complex I in the deactive state","authors":"Ahmed-Noor A. Agip, J. N. Blaza, H. R. Bridges, C. Viscomi, S. Rawson, S. Muench, J. Hirst","doi":"10.2210/PDB6G72/PDB","DOIUrl":"https://doi.org/10.2210/PDB6G72/PDB","url":null,"abstract":"Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recent cryo-EM analyses have produced near-complete models of all 45 subunits in the bovine, ovine and porcine complexes and have identified two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-A structure of complex I from mouse heart mitochondria, a biomedically relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside kinase homolog, and define mechanistically critical elements in the mammalian enzyme. By comparisons with a 3.9-A structure of the 'deactive' state and with known bacterial structures, we identify differences in helical geometry in the membrane domain that occur upon activation or that alter the positions of catalytically important charged residues. Our results demonstrate the capability of cryo-EM analyses to challenge and develop mechanistic models for mammalian complex I.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"548-556"},"PeriodicalIF":16.8,"publicationDate":"2018-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46272166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transient receptor potential vanilloid (TRPV) channels are activated by ligands and heat and are involved in various physiological processes. In contrast to the architecturally related voltage-gated cation channels, TRPV1 and TRPV2 subtypes possess another activation gate at the selectivity filter that can open widely enough to permeate large organic cations. Despite recent structural advances, the mechanism of selectivity filter gating and permeation for both metal ions and large molecules by TRPV1 or TRPV2 is not well known. Here, we determined two crystal structures of rabbit TRPV2 in its Ca2+-bound and resiniferatoxin (RTx)- and Ca2+-bound forms, to 3.9 A and 3.1 A, respectively. Notably, our structures show that RTx binding leads to two-fold symmetric opening of the selectivity filter of TRPV2 that is wide enough for large organic cation permeation. Combined with functional characterizations, our studies reveal a structural basis for permeation of Ca2+ and large organic cations in TRPV2.
{"title":"Conformational plasticity in the selectivity filter of the TRPV2 ion channel.","authors":"L. Zubcevic, S. Le, Huanghe Yang, Seok-Yong Lee","doi":"10.2210/PDB6BWJ/PDB","DOIUrl":"https://doi.org/10.2210/PDB6BWJ/PDB","url":null,"abstract":"Transient receptor potential vanilloid (TRPV) channels are activated by ligands and heat and are involved in various physiological processes. In contrast to the architecturally related voltage-gated cation channels, TRPV1 and TRPV2 subtypes possess another activation gate at the selectivity filter that can open widely enough to permeate large organic cations. Despite recent structural advances, the mechanism of selectivity filter gating and permeation for both metal ions and large molecules by TRPV1 or TRPV2 is not well known. Here, we determined two crystal structures of rabbit TRPV2 in its Ca2+-bound and resiniferatoxin (RTx)- and Ca2+-bound forms, to 3.9 A and 3.1 A, respectively. Notably, our structures show that RTx binding leads to two-fold symmetric opening of the selectivity filter of TRPV2 that is wide enough for large organic cation permeation. Combined with functional characterizations, our studies reveal a structural basis for permeation of Ca2+ and large organic cations in TRPV2.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"405-415"},"PeriodicalIF":16.8,"publicationDate":"2018-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46376461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F. Luo, X. Gui, Heng Zhou, Jinge Gu, Yichen Li, Xiangyu Liu, Minglei Zhao, Dan Li, Xueming Li, Cong Liu
Thermostable cross-β structures are characteristic of pathological amyloid fibrils, but these structures cannot explain the reversible nature of fibrils formed by RNA-binding proteins such as fused in sarcoma (FUS), involved in RNA granule assembly. Here, we find that two tandem (S/G)Y(S/G) motifs of the human FUS low-complexity domain (FUS LC) form reversible fibrils in a temperature- and phosphorylation-dependent manner. We named these motifs reversible amyloid cores, or RAC1 and RAC2, and determined their atomic structures in fibrillar forms, using microelectron and X-ray diffraction techniques. The RAC1 structure features an ordered-coil fibril spine rather than the extended β-strand typical of amyloids. Ser42, a phosphorylation site of FUS, is critical in the maintenance of the ordered-coil structure, which explains how phosphorylation controls fibril formation. The RAC2 structure shows a labile fibril spine with a wet interface. These structures illuminate the mechanism of reversible fibril formation and dynamic assembly of RNA granules.
{"title":"Atomic structures of FUS LC domain segments reveal bases for reversible amyloid fibril formation.","authors":"F. Luo, X. Gui, Heng Zhou, Jinge Gu, Yichen Li, Xiangyu Liu, Minglei Zhao, Dan Li, Xueming Li, Cong Liu","doi":"10.2210/PDB5XRR/PDB","DOIUrl":"https://doi.org/10.2210/PDB5XRR/PDB","url":null,"abstract":"Thermostable cross-β structures are characteristic of pathological amyloid fibrils, but these structures cannot explain the reversible nature of fibrils formed by RNA-binding proteins such as fused in sarcoma (FUS), involved in RNA granule assembly. Here, we find that two tandem (S/G)Y(S/G) motifs of the human FUS low-complexity domain (FUS LC) form reversible fibrils in a temperature- and phosphorylation-dependent manner. We named these motifs reversible amyloid cores, or RAC1 and RAC2, and determined their atomic structures in fibrillar forms, using microelectron and X-ray diffraction techniques. The RAC1 structure features an ordered-coil fibril spine rather than the extended β-strand typical of amyloids. Ser42, a phosphorylation site of FUS, is critical in the maintenance of the ordered-coil structure, which explains how phosphorylation controls fibril formation. The RAC2 structure shows a labile fibril spine with a wet interface. These structures illuminate the mechanism of reversible fibril formation and dynamic assembly of RNA granules.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"341-346"},"PeriodicalIF":16.8,"publicationDate":"2018-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49353881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Gallagher-Jones, C. Glynn, D. Boyer, M. Martynowycz, Evelyn Hernandez, Jennifer Miao, Chih-Te Zee, I. Novikova, Lukasz Goldschmidt, Heather T Mcfarlane, G. Helguera, James E. Evans, M. Sawaya, D. Cascio, D. Eisenberg, T. Gonen, José A. Rodríguez
The atomic structure of the infectious, protease-resistant, β-sheet-rich and fibrillar mammalian prion remains unknown. Through the cryo-EM method MicroED, we reveal the sub-angstrom-resolution structure of a protofibril formed by a wild-type segment from the β2–α2 loop of the bank vole prion protein. The structure of this protofibril reveals a stabilizing network of hydrogen bonds that link polar zippers within a sheet, producing motifs we have named ‘polar clasps’.
{"title":"Sub-ångström cryo-EM structure of a prion protofibril reveals a polar clasp","authors":"M. Gallagher-Jones, C. Glynn, D. Boyer, M. Martynowycz, Evelyn Hernandez, Jennifer Miao, Chih-Te Zee, I. Novikova, Lukasz Goldschmidt, Heather T Mcfarlane, G. Helguera, James E. Evans, M. Sawaya, D. Cascio, D. Eisenberg, T. Gonen, José A. Rodríguez","doi":"10.2210/PDB6AXZ/PDB","DOIUrl":"https://doi.org/10.2210/PDB6AXZ/PDB","url":null,"abstract":"The atomic structure of the infectious, protease-resistant, β-sheet-rich and fibrillar mammalian prion remains unknown. Through the cryo-EM method MicroED, we reveal the sub-angstrom-resolution structure of a protofibril formed by a wild-type segment from the β2–α2 loop of the bank vole prion protein. The structure of this protofibril reveals a stabilizing network of hydrogen bonds that link polar zippers within a sheet, producing motifs we have named ‘polar clasps’.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"25 1","pages":"131-134"},"PeriodicalIF":16.8,"publicationDate":"2018-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45863239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G. Knott, Alexandra East-Seletsky, Joshua C. Cofsky, J. Holton, E. Charles, J. Doudna
{"title":"Guide bound structures of a divergent RNA-targeting A cleaving CRISPR-Cas13a enzyme","authors":"G. Knott, Alexandra East-Seletsky, Joshua C. Cofsky, J. Holton, E. Charles, J. Doudna","doi":"10.2210/PDB5W1I/PDB","DOIUrl":"https://doi.org/10.2210/PDB5W1I/PDB","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"1 1","pages":""},"PeriodicalIF":16.8,"publicationDate":"2017-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48346470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. D. Franceschi, Antti Arjonen, N. Elkhatib, K. Denessiouk, A. Wrobel, T. A. Wilson, J. Pouwels, Guillaume Montagnac, D. Owen, J. Ivaska
We gratefully acknowledge the following funding sources: N.d.F. FinPharma Doctoral Program, Instrumentarium Foundation, Orion Research Foundation, Liv och Halsa foundation, Finsk-Norska Medicinska Stiftelsen and the Magnus Ehrnrooth Foundation; J.I. Academy of Finland CoE, European Research Council Consolidator Grant, the Sigrid Juselius Foundation, The Finnish Heart Foundation and Finnish Cancer Organizations. DJO, AGW and TW are funded by Wellcome Trust fellowship 090909 (DJO).
我们感谢以下资助来源:nd.f FinPharma博士项目、仪器仪器基金会、Orion研究基金会、Liv och Halsa基金会、Finsk-Norska Medicinska Stiftelsen和Magnus Ehrnrooth基金会;芬兰科学院，欧洲研究理事会整合者资助，西格里德·尤西利乌斯基金会，芬兰心脏基金会和芬兰癌症组织。DJO, AGW和TW由惠康信托基金090909 (DJO)资助。
{"title":"Selective Integrin Endocytosis is Driven by Alpha Chain:Ap2 Interactions","authors":"N. D. Franceschi, Antti Arjonen, N. Elkhatib, K. Denessiouk, A. Wrobel, T. A. Wilson, J. Pouwels, Guillaume Montagnac, D. Owen, J. Ivaska","doi":"10.2210/PDB5FPI/PDB","DOIUrl":"https://doi.org/10.2210/PDB5FPI/PDB","url":null,"abstract":"We gratefully acknowledge the following funding sources: N.d.F. FinPharma Doctoral Program, Instrumentarium Foundation, Orion Research Foundation, Liv och Halsa foundation, Finsk-Norska Medicinska Stiftelsen and the Magnus Ehrnrooth Foundation; J.I. Academy of Finland CoE, European Research Council Consolidator Grant, the Sigrid Juselius Foundation, The Finnish Heart Foundation and Finnish Cancer Organizations. DJO, AGW and TW are funded by Wellcome Trust fellowship 090909 (DJO).","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"23 1","pages":"172"},"PeriodicalIF":16.8,"publicationDate":"2016-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68195440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Zubcevic, M. Herzik, B. C. Chung, G. Lander, Seok-Yong Lee
{"title":"Cryo-Electron Microscopy of the Trpv2 Ion Channel","authors":"L. Zubcevic, M. Herzik, B. C. Chung, G. Lander, Seok-Yong Lee","doi":"10.2210/PDB5AN8/PDB","DOIUrl":"https://doi.org/10.2210/PDB5AN8/PDB","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"23 1","pages":"180"},"PeriodicalIF":16.8,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68195129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Crystal Structure of Broadly Neutralizing Antibody CH04, Isolated from Donor CH0219, in Complex with Scaffolded Trimeric HIV-1 Env V1V2 Domain from the Clade AE Strain A244","authors":"J. Gorman, M. Yang, P. Kwong","doi":"10.2210/pdb5esz/pdb","DOIUrl":"https://doi.org/10.2210/pdb5esz/pdb","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"1 1","pages":""},"PeriodicalIF":16.8,"publicationDate":"2015-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68195423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Wallweber, C. Tam, Y. Franke, M. Starovasnik, P. Lupardus
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases, which are essential for proper signaling in immune responses and development. Here we present a 2.0 angstrom resolution crystal structure of a receptor-binding fragment of human TYK2 encompassing the FERM and SH2 domains in complex with a so-called “box2” containing intracellular peptide motif from the IFNα receptor (IFNAR1). The TYK2–IFNAR1 interface reveals an unexpected receptor-binding mode that mimics a SH2 domain–phosphopeptide interaction, with a glutamate replacing the canonical phosphotyrosine residue. This structure provides the first view to our knowledge of a JAK in complex with its cognate receptor and defines the molecular logic through which JAKs evolved to interact with divergent receptor sequences.
{"title":"Structural basis of IFN receptor recognition by TYK2","authors":"H. Wallweber, C. Tam, Y. Franke, M. Starovasnik, P. Lupardus","doi":"10.2210/pdb4po6/pdb","DOIUrl":"https://doi.org/10.2210/pdb4po6/pdb","url":null,"abstract":"Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases, which are essential for proper signaling in immune responses and development. Here we present a 2.0 angstrom resolution crystal structure of a receptor-binding fragment of human TYK2 encompassing the FERM and SH2 domains in complex with a so-called “box2” containing intracellular peptide motif from the IFNα receptor (IFNAR1). The TYK2–IFNAR1 interface reveals an unexpected receptor-binding mode that mimics a SH2 domain–phosphopeptide interaction, with a glutamate replacing the canonical phosphotyrosine residue. This structure provides the first view to our knowledge of a JAK in complex with its cognate receptor and defines the molecular logic through which JAKs evolved to interact with divergent receptor sequences.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"21 1","pages":"443"},"PeriodicalIF":16.8,"publicationDate":"2014-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68194115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaohua Lou, G. Toresson, Cindy Benod, J. Suh, Kevin J Philips, P. Webb, J. Gustafsson
{"title":"Structure of the retinoid X receptor alpha-liver X receptor beta (RXR alpha-LXR beta ) heterodimer on DNA.","authors":"Xiaohua Lou, G. Toresson, Cindy Benod, J. Suh, Kevin J Philips, P. Webb, J. Gustafsson","doi":"10.2210/PDB4NQA/PDB","DOIUrl":"https://doi.org/10.2210/PDB4NQA/PDB","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"21 1","pages":"277-281"},"PeriodicalIF":16.8,"publicationDate":"2014-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68193982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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