The crystal structure of a human PP2A phosphatase activator reveals a novel fold and highly conserved cleft implicated in protein-protein interactions.
Protein phosphatase 2A (PP2A) is a heterotrimeric Ser/Thr phosphatase that is involved in regulating a plethora of signaling pathways in the cell, making its regulation a critical part of the well being of the cell. For example, three of the non-catalytic PP2A subunits have been linked to carcinogenic events. Therefore, the molecular basis for the complicated protein-protein interaction pattern of PP2A and its regulators is of special interest. The PP2A phosphatase activator (PTPA) protein is highly conserved from humans to yeast. It is an activator of PP2A and has been shown to be essential for a fully functional PP2A, but its mechanism of activation is still not well defined. We have solved the crystal structure of human PTPA to 1.6A. It reveals a two-domain protein with a novel fold comprised of 13 alpha-helices. We have identified a highly conserved cleft as a potential region for interaction with peptide segments of other proteins. Binding studies with ATP and its analogs are not consistent with ATP being a cofactor/substrate for PTPA as had previously been proposed. The structure of PTPA can serve as a basis for structure-function studies directed at elucidating its mechanism as an activator of PP2A.
Magnusdottir
Audur
A
Department of Biochemistry and Biophysics, Stockholm University 10691 Stockholm, Sweden.
Stenmark
Pål
P
Flodin
Susanne
S
Nyman
Tomas
T
Hammarström
Martin
M
Ehn
Maria
M
Bakali H
M Amin
MA
Berglund
Helena
H
Nordlund
Pär
P
D000255:Adenosine Triphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
D011506:Proteins; D000255:Adenosine Triphosphate; D010749:Phosphoprotein Phosphatases; C087440:PTPA protein, human