Heterotrimeric G Protein Cycle
Updated 23 February 2004: Animation Now Available

Anita M. Preininger and Heidi E. Hamm^*

¹ Department of Pharmacology, Vanderbilt University Medical Center, Nashville TN 37232-6600, USA.

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*Corresponding author. E-mail: heidi.hamm{at}vanderbilt.edu

Description

Animation. Heterotrimeric G protein cycle. This animation shows the basic heterotrimeric G protein cycle and allows the user to then add three different regulators of the cycle, an RGS (regulator of G protein signaling) protein, a GDI (guanine nucleotide dissociation inhibitor) protein, or a guanine nucleotide exchange factor (GEF). G proteins are comprised of two subunits, and an obligate dimer βγ. The basic cycle shows a G protein-coupled receptor (GPCR) activating the G protein by promoting the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP), which allows the and βγ subunits to separate and activate downstream targets. The signal is terminated when the subunit hydrolyzes GTP and the and βγ subunits reassociate. RGS stimulates the GTPase activity of the subunit and terminates signaling faster. GDI prevents the dissociation of GDP from the subunit and blocks reassociation of the βγ subunit, thus extending βγ signaling. GEF enhances the rate of GTP loading in the presence of an activated receptor thus accelerating the speed of the response. The animation allows the user to choose to play the cycle with or without the added regulators and see the effect on the signaling duration. Notice that the action is predominantly localized near the plasma membrane and that βγ are tethered to the plasma membrane by a posttranslationally added lipid anchor.

Press "Play" to start the basic G protein cycle in the absence of any regulators other than the receptor. Press the RGS symbol to add RGS; press the GDI symbol to add GDI; press the GEF symbol to add GEF.

These animations were created by Julie White with scientific oversight of A. M. Preininger and H. E. Hamm in the Department of Pharmacology, Vanderbilt University Medical Center.

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Movie. Conformational changes associated with GTP binding and hydrolysis. This movie starts with the inactive guanosine diphosphate (GDP)-bound form of the subunit of bovine transducin (G_t) bound to the βγ subunit shown in grey. In the G subunit, the helical domain is shown in red, and the GTPase domain is shown in green. The exchange of GDP for guanosine triphosphate (GTP) is followed by the changes associated with GTPase activity. Upon GTP binding and hydrolysis, regions in yellow color (switch regions) undergo dramatic conformational changes. Note the opening and closing of the switch regions that accompanies the GDP- and GTP-bound states.

The movie was created by Cameron Slayden with the oversight of A. Preininger and H. E. Hamm and is based on crystal structures. The inactive GDP-bound state of G is based on PDB file 1TAG, the βγ is based on PDB file 1TBG, the active GTP-bound state is represented by the structure with the nonhydrolyzable analog GTPγS (PDB file 1TND), and the transition state between GTP-bound and GDP-bound state is represented by G_t bound to GDP-AlF₄^– (PDB file 1TAD), which is a transition state mimetic. The GDP-bound structure was morphed into each of the other structures by computer to provide an idea of how nucleotide binding and hydrolysis contribute to changes in structure during the G protein activation and inactivation cycle. The slow step in the overall cycle of activation and hydrolysis is the release of GDP.

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Educational Details

Learning Resource Type: Animation

Context: Undergraduate upper division, graduate, professional (degree program)

Intended Users: Teacher, learner

Intended Educational Use: Teach, learn

Discipline: Cell biology, structural biology

Keywords: Signal transduction, GPCR, structure, crystallography

Technical Details

Format: Shockwave Flash Object (swf file) (animation); Video file (avi file) (movie)

Size: 90 kb (animation); 8.9 MB (movie)

Requirements: Macromedia Flash 5 (animation); Windows Media Player or similar movie player (movie)

Related Resources

Review: A. M. Preininger, H. E. Hamm, G protein signaling: Insights from new structures. Sci. STKE 2004, re3 (2004). [Gloss] [Abstract] [Full Text]

Limits for Use

Cost: Free

Rights: This material may be downloaded, printed, linked to, and/or redistributed without modification for non-commercial, course teaching purposes only, provided credit to STKE is included by listing the citation for the teaching resource.

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Citation: Review: A. M. Preininger, H. E. Hamm, G protein signaling: Insights from new structures. Sci. STKE 2004, re3 (2004).

© 2004 American Association for the Advancement of Science