Protein Phosphatase 2A with C-terminus truncated catalytic subunit
Homo sapiens (human)
Control of protein phosphorylation and dephosphorylation is fundamental for regulating all aspects of cell function. Protein Phosphatase 2A (PP2A) is a major serine/threonine phosphatase involved in many essential aspects of cellular physiology. The phosphorylation and dephosphorylation of a serine or a threonine side chain regulate transmembrane signal transduction, intracellular signal amplification and cell-cycle control.
PP2A is also an important tumor suppressor protein. Mutations in the scaffolding subunit of the PP2A complex had been reported to be linked to a variety of primary human tumors. The mutations cause compromised interaction between subunits resulting in decreasing the dephosphorylation activity. The crystal structure of PP2A will support the understanding.
Protein Phosphatase 2A (PP2A) is a heterotrimeric holoenzyme, which comprises a scaffolding subunit, a catalytic subunit and a regulatory subunit. A complex of the scaffolding subunit and the catalytic subunit is called core enzyme and its structure has been already solved (xPSSS:2IE3). There are several regulatory subunits divided in four subfamilies with at least 16 members in these subfamilies.
Here the crystal structure of PP2A involving the regulatory subunit B’/B56/PR61 has been solved (xPSSS:2NPP). Surprisingly, the B’/B56/PR61 subunit has a HEAT-like (huntingtin-elongation-A subunit-TOR-like) repeat structure (Fig. 1), similar to that of the scaffolding subunit. The regulatory subunit binds to the other subunits. It uses its own ridge to bind to the catalytic subunit; in the meantime, the hydrophobic convex side of the regulatory subunit recognizes the ridge of the scaffolding subunit (Fig. 2). Thus, negatively charged concave surface is exposed and it is possible that the regulatory subunit use the acidic surface for substrates recognition. By comparing between core enzyme and holoenzyme, it was revealed that the scaffolding subunit undergo a conformational change from L-shape structure to C-shape. The switching point is in its HEAT repeat 11.
Previously, methylation of the C-terminus of the catalytic subunit was thought to play an important role in holoenzyme assembly. However, this effect cannot be significant because of other crystal structures (this structure (xPSSS:2NYM) and xPSSS:2NYL) which catalytic subunits have truncated C terminus.
The understanding of PP2A function and regulation based on the structure is expected.
||(Fig. 1) HEAT repeat|
HEAT repeats comprise a pair of antiparallel α helices, as the HEAT repeat 4 of the regulatory subunit (LEU186～ASN223) shown here.
||(Fig. 2) The structure of PP2A|
The PP2A holoenzyme comprises a scaffolding subunit (red), a catalytic subunit (blue) and a regulatory subunit (yellow).
Note, however, that the C-terminus of the catalytic subunit in this structure (xPSSS:2NYM) is truncated.
The scaffolding subunit has 15 HEAT repeats
and the regulatory subunit 8.
Protein Data Bank (PDB)
Xu, Y. Xing, Y. Chen, Y. Chao, Y. Lin, Z. Fan, E. Yu, J.W. Strack, S. Jeffrey, P.D. Shi, Y.; "Structure of the Protein Phosphatase 2A Holoenzyme."; Cell; (2006) 127:1239-1251 PubMed:17174897.
- xPSSS:2NYL PP2A with C-terminus truncated catalytic subunit
author: Naoya Fujita