蛋白激酶A RⅡβ结构及功能的研究进展

Progress of the function and mechanism of protein kinase A RⅡβ

蛋白激酶A(PKA)是由1个调节亚基(R亚基)二聚体和两个催化亚基(C亚基)组成的四聚体,全酶无活性。R亚基有RⅠα、RⅠβ、RⅡα和RⅡβ4种亚型,分别具有不同的理化性质。RⅡβ亚基氨基端包含1个二聚化/对接结构域,PKA通过此结构域与腺苷酸激酶锚定蛋白结合锚定于细胞的特定位点。羧基端是两个串联的高度保守的环核苷酸结构域,与PKA全酶解聚以及激活有关。两个RC异二聚体通过RⅡβ亚基中的β4~β5环相锚定。细胞质中存在足够的Mg ATP时将导致RⅡβ亚基自身磷酸化。RⅡβ在特定组织表达,主要表达于内分泌腺、脑和脂肪组织。生物信息学分析表明,RⅡβ与其他R亚基的序列有很大差别,只有大约50%的序列相同,提示RⅡβ可能具有不同的生物学功能。因此,目前对PKA RⅡβ的功能及其作用机制的研究已逐渐成为热点。

Protein kinase A （PKA） exists in mammalian cells as an inactive tetrameric holoenzyme composed of a regulatory （R） subunit dimer and two catalytic （C） subunits. There are four isoforms of the R subunits, RIα, RⅡβ, RⅡα, and RⅡβ. Each of them has special physieochemical property. RⅡβ subunit contains an N-terminal dimerization/ docking domain. PKA is anchored to specific sites in the cell by binding of an adenosine kinase-anchoring protein amphipathic helix to the dimerization/docking domain. At the C terminus there are two tandem highly conserved cyclic nueleotide-binding domains, which relate to depolymerization and activation of the holoenzyme. The heterodimers are anchored together by an interface created by the β4-β5 loop in the RⅡβ subunit. In cells the inactive R RⅡβ2：C2 holoenzyme once formed, it may be primed to have its R subunits autophosphory when high availability of cytoplasmic MgATP is given. RⅡβ expression is tissue specific, mainly in the brain, adipose tissue and endocrine organs. Bioinformatics analysis has showed that the sequence of RⅡβ is significantly different from other three R subunit isoforms. The big difference indicates that PKA RⅡβ may have special biological function. Therefore many researchers focus on the function and mechanism of PKA RⅡβ.