G-protein signaling leverages subunit-dependent membrane affinity to differentially control βγ translocation to intracellular membranes

被引:37
作者
O'Neill, Patrick R. [1 ]
Karunarathne, W. K. Ajith [1 ]
Kalyanaraman, Vani [1 ]
Silvius, John R. [2 ]
Gautam, N. [1 ,3 ]
机构
[1] Washington Univ, Sch Med, Dept Anesthesiol, St Louis, MO 63110 USA
[2] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[3] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA
基金
美国国家卫生研究院;
关键词
protein-membrane interaction; spatio-temporal dynamics; G protein-coupled receptors; HETEROTRIMERIC G-PROTEINS; PLASMA-MEMBRANE; COMPLEX TRANSLOCATION; RECEPTOR ACTIVATION; GOLGI-COMPLEX; PRENYLATED PROTEINS; POLYBASIC DOMAIN; RAS; TRAFFICKING; ACYLATION;
D O I
10.1073/pnas.1205345109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Activation of G-protein heterotrimers by receptors at the plasma membrane stimulates beta gamma-complex dissociation from the alpha-subunit and translocation to internal membranes. This intermembrane movement of lipid-modified proteins is a fundamental but poorly understood feature of cell signaling. The differential translocation of G-protein beta gamma-subunit types provides a valuable experimental model to examine the movement of signaling proteins between membranes in a living cell. We used live cell imaging, mathematical modeling, and in vitro measurements of lipidated fluorescent peptide dissociation from vesicles to determine the mechanistic basis of the intermembrane movement and identify the interactions responsible for differential translocation kinetics in this family of evolutionarily conserved proteins. We found that the reversible translocation is mediated by the limited affinity of the beta gamma-subunits for membranes. The differential kinetics of the beta gamma-subunit types are determined by variations among a set of basic and hydrophobic residues in the gamma-subunit types. G-protein signaling thus leverages the wide variation in membrane dissociation rates among different gamma-subunit types to differentially control beta gamma-translocation kinetics in response to receptor activation. The conservation of primary structures of gamma-subunits across mammalian species suggests that there can be evolutionary selection for primary structures that confer specific membrane-binding affinities and consequent rates of intermembrane movement.
引用
收藏
页码:E3568 / E3577
页数:10
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