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A molecular and structural mechanism for G protein-mediated microtubule destabilization.

ABSTRACT: The heterotrimeric, G protein-coupled receptor-associated G protein, G?(s), binds tubulin with nanomolar affinity and disrupts microtubules in cells and in vitro. Here we determine that the activated form of G?(s) binds tubulin with a K(D) of 100 nm, stimulates tubulin GTPase, and promotes microtubule dynamic instability. Moreover, the data reveal that the ?3-?5 region of G?(s) is a functionally important motif in the G?(s)-mediated microtubule destabilization. Indeed, peptides corresponding to that region of G?(s) mimic G?(s) protein in activating tubulin GTPase and increase microtubule dynamic instability. We have identified specific mutations in peptides or proteins that interfere with this process. The data allow for a model of the G?(s)/tubulin interface in which G?(s) binds to the microtubule plus-end and activates the intrinsic tubulin GTPase. This model illuminates both the role of tubulin as an "effector" (e.g. adenylyl cyclase) for G?(s) and the role of G?(s) as a GTPase activator for tubulin. Given the ability of G?(s) to translocate intracellularly in response to agonist activation, G?(s) may play a role in hormone- or neurotransmitter-induced regulation of cellular morphology.

SUBMITTER: Dave RH

PROVIDER: S-EPMC3039364 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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A molecular and structural mechanism for G protein-mediated microtubule destabilization.

Davé Rahul H RH Saengsawang Witchuda W Lopus Manu M Davé Sonya S Wilson Leslie L Rasenick Mark M MM

The Journal of biological chemistry 20101126 6

The heterotrimeric, G protein-coupled receptor-associated G protein, Gα(s), binds tubulin with nanomolar affinity and disrupts microtubules in cells and in vitro. Here we determine that the activated form of Gα(s) binds tubulin with a K(D) of 100 nm, stimulates tubulin GTPase, and promotes microtubule dynamic instability. Moreover, the data reveal that the α3-β5 region of Gα(s) is a functionally important motif in the Gα(s)-mediated microtubule destabilization. Indeed, peptides corresponding to ...[more]

PMID: 21112971

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Project description:Glucocorticoid, a major risk factor of Alzheimer's disease (AD), is widely known to promote microtubule dysfunction recognized as the early pathological feature that culminates in memory deficits. However, the exact glucocorticoid receptor (GR)-mediated mechanism of how glucocorticoid triggers microtubule destabilization and following intracellular transport deficits remains elusive. Therefore, we investigated the effect of glucocorticoid on microtubule instability and cognitive impairment using male ICR mice and human neuroblastoma SH-SY5Y cells. The mice group that was exposed to corticosteroid, the major glucocorticoid form of rodents, showed reduced trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) 1/2 and mitochondria, which are necessary for memory establishment, into the synapse due to microtubule destabilization. In SH-SY5Y cells, cortisol, the major glucocorticoid form of humans, also decreased microtubule stability represented by reduced acetylated α-tubulin to tyrosinated α-tubulin ratio (A/T ratio), depending on the mitochondria GR-mediated pathway. Cortisol translocated the Hsp70-bound GR into mitochondria which thereafter promoted GR-Bcl-2 interaction. Increased ER-mitochondria connectivity via GR-Bcl-2 coupling led to mitochondrial Ca2+ influx, which triggered mTOR activation. Subsequent autophagy inhibition by mTOR phosphorylation increased SCG10 protein levels via reducing ubiquitination of SCG10, eventually inducing microtubule destabilization. Thus, failure of trafficking AMPAR1/2 and mitochondria into the cell terminus occurred by kinesin-1 detachment from microtubules, which is responsible for transporting organelles towards periphery. However, the mice exposed to pretreatment of microtubule stabilizer paclitaxel showed the restored translocation of AMPAR1/2 or mitochondria into synapses and improved memory function compared to corticosterone-treated mice. In conclusion, glucocorticoid enhances ER-mitochondria coupling which evokes elevated SCG10 and microtubule destabilization dependent on mitochondrial GR. This eventually leads to memory impairment through failure of AMPAR1/2 or mitochondria transport into cell periphery.

Dataset Information

A molecular and structural mechanism for G protein-mediated microtubule destabilization.

Publications

A molecular and structural mechanism for G protein-mediated microtubule destabilization.

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