Protein Name

Protein phosphatase 2A (heterotrimeric holoenzyme)


Homo sapiens (human)

Biological Context

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.

Structure Description


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.

(Fig.1) PP2A heterotrimeric holoenzyme (Fig.2) HEAT repeat

A-C interface

The A and C subunits form a stable AC core dimer. A subunit makes extensive interactions with the C subunit through the A subunit HEAT repeat A11-A15. In the residues which construct a series of interactions, it is thought that K416, R418, and V533 of the A subunit are important. Actually, residue mutations disrupting the A-C interaction were found in cancer patients. (Fig.3).

pp2a3 Five HEAT repeats(A11-A15) of the A subunit (blue) make
interactions with the C subunit (pink). Interactions formed with
residues(yellow) is considered as important for A-C binding.
(Fig.3) A-C interface

A-B interface

A and B subunits cannot directly form a stable complex. The weak binding between A and B subunits is enhanced by binding of the methylated C-terminal tail to this interface. (Fig.4).

pp2a4 The C-terminal tail (pink) mediate the binding of A subunit(blue)
and B subunit(green).
(Fig.4) A-B interface

B-C interface

The substrate-binding site exists near the interface between B subunit and C subunit. When different kinds of B subunit bind to C subunit, the environment around the substrate-binding site should change slightly. That is, B subunit has critical role in substrate-binding and substrate specificity. (Fig.5).

pp2a5 PP2A-inhibitor(purple) binding site is close to interface
between A subunit and B subunit.
(Fig.5) B-C interface

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).

(Fig.6) Schematic view of heterotrimer organization
and substrate reception

(*) 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.


  • PDB:2NYM PP2A (with C-terminus truncated catalytic subunit)

author: Jun-ichi Ito

Japanese version:PDB:2IAE