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Heterotrimeric G proteins
Voet, Biochemistry
90º
• three subunits: , associate only in GDP form• subunit = GTPase• & 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)
G proteins
Voet, Biochemistry
• at least 27 different Gproteins in humans
• three Switch regions
• extra helical domain inserted into canonical G domain
Gt (transducin) – involved in vision
G protein coupled Receptors
Voet, Biochemistry
G protein coupled receptors (GPCR):
• 7 transmembrane receptors
• GEF for heterotrimeric G proteins
• activation of G induces dissociation of G
• large class of receptors, e.g. for epinephrine (adrenergic receptors), odorant molecules, light (rhodopsin)
Gi1-RGS4 complex
Tesmer, Cell 1997
• Gi1-Mg2+-GDP-AlF4- -RGS4
• 2.8 Å, molecular replacement using Gi1-GDP-AlF4- structure
• Rcryst = 29%, Rfree = 21%
RGS4 contacts all switch regions of Gi1 with the bottom of its four-helix bundle
Interface between RGS4 & Gi1
Tesmer, Cell 1997
RGS4 loop 3-4, loop 5-6 and loop 7-8 interact with all three switch regions of Gi1
RGS4 reduces the flexibility of all three switch regions (comparison of B factors of this structure with Gi1 alone)
Active Site of Gi1
Tesmer, Cell 1997
• 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
Visual preception
Lodish, 5th edition
Rhodopsin is activated by light
Acts as GEF for transducin (G only found in rod cells)
Phototransduction cascade
Lodish, 5th edition
Rhodopsin Transducin (Gta) cGMP phosphodiesterase (PDE) cGMP GMP cGMP dissociates from nucleotide-gated channel Channel closes Hyperpolarization of membrane
Light Detection by Retinal
Lodish, 5th edition
Retinal is covalently bound to Rhodopsin
Isomerization of Retinal results in conformational change of rhodopsin (activation)
Organization of the olfactory system
Olfactory cortex
Main olfactory bulb
Sensory neurons in Olfactory ephithelium
Nasal cavity