Protein phosphatase 1

Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen metabolism, muscle contraction, cell progression, neuronal activities, splicing of RNA, mitosis, cell division, apoptosis, protein synthesis, and regulation of membrane receptors and channels. Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen metabolism, muscle contraction, cell progression, neuronal activities, splicing of RNA, mitosis, cell division, apoptosis, protein synthesis, and regulation of membrane receptors and channels. Each PP1 enzyme contains both a catalytic subunit and at least one regulatory subunit. The catalytic subunit consists of a 30-kD single-domain protein that can form complexes with other regulatory subunits. The catalytic subunit is highly conserved among all eukaryotes, thus suggesting a common catalytic mechanism. The catalytic subunit can form complexes with various regulatory subunits. These regulatory subunits play an important role in substrate specificity as well as compartmentalization. Some common regulatory subunits include GM (PPP1R3A) and GL (PPP1R3B), which are named after their locations of action within the body (Muscle and Liver respectively). While the yeast S. cerevisiae only encodes one catalytic subunit, mammals have four isozymes encoded by three genes, each attracting a different set of regulatory subunits. X-ray crystallographic structural data is available for PP1 catalytic subunit. The catalytic subunit of PP1 forms an α/β fold with a central β-sandwich arranged between two α-helical domains. The interaction of the three β-sheets of the β-sandwich creates a channel for catalytic activity, as it is the site of coordination of metal ions. These metal ions have been identified as Mn and Fe and their coordination is provided by three histidines, two aspartic acids, and one asparagine. The mechanism involves two metal ions binding and activating water, which initiates a nucleophilic attack on the phosphorus atom. Regulation of these different processes is performed by distinct PP1 holoenzymes that facilitate the complexation of the PP1 catalytic subunit to various regulatory subunits. Potential inhibitors include a variety of naturally occurring toxins including okadaic acid, a diarrhetic shellfish poison, strong tumor promoter, and microcystin. Microcystin is a liver toxin produced by blue-green algae and contains a cyclic heptapeptide structure that interacts with three distinct regions of the surface of the catalytic subunit of PP1. The structure of MCLR does not change when complexed with PP1, but the catalytic subunit of PP1 does in order to avoid steric effects of Tyr 276 of PP1 and Mdha side chain of MCLR.