title: Structure of the N-terminal domain of GRP94. Basis for ligand specificity and regulation.
abstract: GRP94, the endoplasmic reticulum (ER) paralog of the chaperone Hsp90, plays an essential role in the structural maturation or secretion of a subset of proteins destined for transport to the cell surface, such as the Toll-like receptors 2 and 4, and IgG, respectively. GRP94 differs from cytoplasmic Hsp90 by exhibiting very weak ATP binding and hydrolysis activity. GRP94 also binds selectively to a series of substituted adenosine analogs. The high resolution crystal structures at 1.75-2.1 A of the N-terminal and adjacent charged domains of GRP94 in complex with N-ethylcarboxamidoadenosine, radicicol, and 2-chlorodideoxyadenosine reveals a structural mechanism for ligand discrimination among hsp90 family members. The structures also identify a putative subdomain that may act as a ligand-responsive switch. The residues of the charged region fold into a disordered loop whose termini are ordered and continue the twisted beta sheet that forms the structural core of the N-domain. This continuation of the beta sheet past the charged domain suggests a structural basis for the association of the N-terminal and middle domains of the full-length chaperone.
authors.affiliation: Departments of Biochemistry and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Soldano
authors.forename: Arif
authors.initials: A
authors.lastname: Jivan
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Nicchitta
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Gewirth
mesh_terms: D000241:Adenosine / Q000737:chemistry; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D019281:Dimerization; D004285:Dogs; D004583:Electrons; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D007783:Lactones / Q000737:chemistry; D008024:Ligands; D018942:Macrolides; D008565:Membrane Proteins / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D008024:Ligands; D018942:Macrolides; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; C018551:glucose-regulated proteins; C055504:2-chloro-2',3'-dideoxyadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); D016048:Dideoxyadenosine; D005982:Glutathione Transferase; C035359:monorden; D000241:Adenosine