title: Structural Basis of Neurohormone Perception by the Receptor Tyrosine Kinase Torso.
abstract: In insects, brain-derived Prothoracicotropic hormone (PTTH) activates the receptor tyrosine kinase (RTK) Torso to initiate metamorphosis through the release of ecdysone. We have determined the crystal structure of silkworm PTTH in complex with the ligand-binding region of Torso. Here we show that ligand-induced Torso dimerization results from the sequential and negatively cooperative formation of asymmetric heterotetramers. Mathematical modeling of receptor activation based upon our biophysical studies shows that ligand pulses are "buffered" at low receptor levels, leading to a sustained signal. By contrast, high levels of Torso develop the signal intensity and duration of a noncooperative system. We propose that this may allow Torso to coordinate widely different functions from a single ligand by tuning receptor levels. Phylogenic analysis indicates that Torso is found outside arthropods, including human parasitic roundworms. Together, our findings provide mechanistic insight into how this receptor system, with roles in embryonic and adult development, is regulated.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Jenni
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Goyal
authors.affiliation: The Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: von Grotthuss
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Stanislav Y
authors.initials: SY
authors.lastname: Shvartsman
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA. Electronic address: klein@crystal.harvard.edu.
authors.forename: Daryl E
authors.initials: DE
authors.lastname: Klein
mesh_terms: D000818:Animals; D001665:Binding Sites; D012831:Bombyx / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007301:Insect Hormones / Q000737:chemistry* / Q000378:metabolism*; D019476:Insect Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010802:Phylogeny; D055503:Protein Multimerization; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D053722:Receptors, Interleukin-17 / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D007301:Insect Hormones; D019476:Insect Proteins; D053722:Receptors, Interleukin-17; C009089:prothoracicotropic hormone; D020794:Receptor Protein-Tyrosine Kinases