Protein phosphatase 2A (heterotrimeric holoenzyme)
Homo sapiens (human)
Phosphorylation and dephosphorylation of proteins are fundamental mechanisms for cell regulation. Protein phosphatase 2A (PP2A), which hydrolyzes phosphate group attached to Ser/Thr residue side chain, is concerned with regulation of cell cycle and cellular signalling. PP2A is a heterotrimeric holoenzyme composed of AC core enzyme and regulatory B subunits. AC core enzyme is a complex of scaffold A subunit and catalytic C subunit. 18 kinds of regulatory B subunits have been identified. Based on sequence homology, they can be classified into B(PR55), B'(B56), and B''(PR72) families. The catalytic C subunit contains a catalytic domain that shares sequence homology with other Ser/Thr phosphatases (PP1, PP2B, PP4, PP6). The deregulation of PP2A is associated with multiple human cancers and Alzheimer's disease. However, the regulatory mechanism of trimeric assembly and substrate recruitment remains unclear. The crystal structure of PP2A holoenzyme solved presented here is very important for understanding these mechanisms.
The human PP2A holoenzyme cristal structure reported here is a complex of A, B56, C subunits and the PP2A inhibitor. (Fig.1). The A subunit contains 15 HEAT repeats, forming a horseshoe shape. Each HEAT repeat consists of two anti-parallel α-helices connected by an inter-repeat loops. (Fig.2). There is a substantial conformational change from the twisted hook shape of the monomeric structure to a more closed C-shape of the trimeric structure of the A subunit. B subunit also contains eight pseudo HEAT repeats. C subunit forms a compact ellipsoidal structure and contains 2 Mn2+ ions. Interfaces between each subunit are detailed below.
From the observations described above, PP2A can form a trimer and is capable of substrate reception by a mechanism described as follows. First, C-terminal tail of C subunit can bind to highly negatively charged surface of the A subunit by methylated. Thereby the binding of the B subunit to the AC core enzyme is promoted (*). Next, by the binding of B subunit to AC core enzyme, substrate-binding site structurally change and can receive substrate. (Fig.6).
(*) According to the experiment of Xu and others, even if C-terminal tail of C subunit of PP2A (humans) was removed, the trimer was formed (PDB:2NYM). They propose that C-terminal tail of C subunit is not essential for trimer-forming.
Protein Data Bank (PDB)
Cho, U.S. Xu, W.; "Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme."; Nature; (2007) 445:53-57 PubMed:17086192.
author: Jun-ichi Ito