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G Proteins - Part 2

G Proteins - Part 2. Biochemistry 4000 Dr. Ute Kothe. Ras-activated MAP kinase cascade. Voet, Biochemistry. Heterotrimeric G proteins. three subunits: a, b, g , associate only in GDP form a subunit = GTPase a & g subunits are linked to membrane by covalently attached lipids

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G Proteins - Part 2

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  1. G Proteins- Part 2 Biochemistry 4000 Dr. Ute Kothe

  2. Ras-activated MAP kinase cascade Voet, Biochemistry

  3. Heterotrimeric G proteins • three subunits: a, b, g, associate only in GDP form • a subunit = GTPase • a & g subunits are linked to membrane by covalently attached lipids • become activated by membrane receptor (GEF) • become inactivated by “special GAPs” called Regulators of G • protein signaling (RGS) 90º Voet, Biochemistry

  4. Ga proteins • at least 27 different Ga proteins in humans • three Switch regions • extra helical domain inserted into canonical G domain Gta (transducin) – involved in vision Voet, Biochemistry

  5. G protein coupled Receptors • G protein coupled receptors (GPCR): • 7 transmembrane receptors • GEF for heterotrimeric G proteins • activation of Ga induces dissociation of Gbg • large class of receptors, e.g. for epinephrine (adrenergic receptors), odorant molecules, light (rhodopsin) Voet, Biochemistry

  6. Activation & Inhibition of Adenyl Cyclase (AC) by Ga proteins Voet, Biochemistry

  7. Gia1-RGS4 complex • Gia1-Mg2+-GDP-AlF4- -RGS4 • 2.8 Å, molecular replacement using Gia1-GDP-AlF4- structure • Rcryst = 29%, Rfree = 21% RGS4 contacts all switch regions of Gia1 with the bottom of its four-helix bundle Tesmer, Cell 1997

  8. Interface between RGS4 & Gia1 RGS4 loop 3-4, loop 5-6 and loop 7-8 interact with all three switch regions of Gia1 RGS4 reduces the flexibility of all three switch regions (comparison of B factors of this structure with Gia1 alone) Tesmer, Cell 1997

  9. Active Site of Gia1 • no catalytic residue added • by RGS4 • GTPase activation by • stabilization of the switch • regions, i.e. stabilization of • the transition state • RGS4-Asn128 might • facilitate GTP hydrolysis • either by stabilizing Gln 204 or • by orienting the attacking H2O • catalytic Arginine 178 provided • in cis Tesmer, Cell 1997

  10. Visual preception Rhodopsin is activated by light Acts as GEF for transducin (Ga only found in rod cells) Lodish, 5th edition

  11. Phototransduction cascade • Rhodopsin • Transducin (Gta) • cGMP phosphodiesterase (PDE) • cGMP GMP • cGMP dissociates from nucleotide-gated channel • Channel closes • Hyperpolarization of membrane Lodish, 5th edition

  12. Light Detection by Retinal Retinal is covalently bound to Rhodopsin Isomerization of Retinal results in conformational change of rhodopsin (activation) Lodish, 5th edition

  13. Organization of the olfactory system Olfactory cortex Main olfactory bulb Sensory neurons in Olfactory ephithelium Nasal cavity

  14. Olfactory signal transduction • Odorant Receptors: • discovered in 1991 • Nobel prize for Linda Buck & Richard Axel 2004 • GPCRs • largest multigene • family • ~ 350 in human • ~ 1000 in mice • (1-3 % of the genes)

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