The Function of JPH3 and PPP2R2B

Could the HDL2 or SCA12 repeats have an impact on gene expression? This possibility is intriguing because of the known functions of JPH3 and PPP2R2B. JPH3 encodes one member of a four protein family (Takeshima et al. 2000; Nishi et al. 2000, 2003). Whereas JPH1 is expressed in skeletal muscle and JPH2 is expressed in cardiac and skeletal muscle, JPH3, along with JPH4 (Nishi et al. 2003), is expressed in brain and to a much lesser extent in testes. While detailed studies of JPH3 expression have not been performed, JP3 (the mouse orthologue of JPH3) is widely expressed in the brain, with high density in hippocampus, cerebral cortex, striatum, and cerebellar cortex (Nishi et al. 2003).

The N-terminus of each junctophilin contains a series of repeating tracts, each 14 amino acids in length, termed membrane orientation and recognition nexus (MORN) motifs that serve to anchor the N-terminus of the protein to the plasma membrane. The junctophilins also have an endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) transmembrane domain, which serves to anchor the C-terminus to the ER or the SR (Takeshima et al. 2000). This structure suggested that the junctophilins may tether plasma membrane to the ER/SR, placing plasma membrane voltage sensors adjacent to ER/SR ion channels, particularly ryanodine and IP3 receptor-gated calcium channels (Fig. 7). Consistent with this hypothesis, the junctional complexes in JP1 knockout mice (Ito et al. 2001), compared with controls, were fewer in number and structurally abnormal, muscle response to electrical stimulation was impaired, and muscle response to calcium was abnormal. The implication is that loss of JPH3 expression in brain could similarly impair neuronal function, and perhaps survival, through destabilization of calcium flux.

Like JPH3, the function of PPP2R2B has been partially established. It is one of multiple alternative regulatory units of the ubiquitous enzyme protein phosphatase 2A (PP2A, also termed PP2). PP2A has been implicated in a plethora of cellular processes, including oncogenesis, growth and differentiation, DNA replication, morphogenesis and cytokinesis, regulation of kinase cascades, ion channel function, neurotransmitter release, microtubule assembly, and apoptosis (Janssens et al. 2005; Price and Mumby 1999; Santoro and plasma membrane

ER membrane extracellular space extracellular space

Voltage sensor

\IP3 receptor

Fig. 7 Junctophilin function. Putative role of junctophilin in bridging the gap between the plasma membrane and the endoplasmic reticulum (ER), bringing plasma membrane voltage sensors into the proximity of IP3 receptors that modulate calcium release from the ER. Junctophilin membrane orientation and recognition nexus motifs (MORN), which serve to anchor junctophilin to the inner plasma membrane, and the ER transmembrane domain (TM) are indicated. (Adapted from Takeshima et al. 2000)

Grummt 2001; Virshup 2000). PP2A is trimeric in structure, and includes a catalytic subunit (PP2Ac or subunit C; two known isoforms), a structural subunit (PR65 or subunit A; two known isoforms), and a regulatory subunit (more than 12 known isoforms divided into three families) (Fig. 8). The structural and catalytic subunits form a complex to which, in a highly regulated process, one of the regulatory subunits is recruited. As many as 75 different trimeric combinations may exist. The structural and catalytic subunits are constitutively expressed in all mammalian cells, whereas expression of the regulatory subunits is spatially and temporally restricted. It is the regulatory subunits that confer much of the substrate specificity and intracellular targeting to the entire enzyme complex (McCright et al. 1996; Millward et al. 1999; Tehrani et al. 1996; Virshup, 2000).

PPP2R2B encodes a protein usually termed PR55P or B^ (Mayer et al. 1991) that is widely and specifically expressed in neurons throughout the brain (Strack et al. 1998). The PPP2R2 family of subunits, which includes PPP2R2B, regulate PP2A dephosphorylation of, among other substrates, vimentin (Tur-owski et al. 1999), histone-1 (Ferrigno et al. 1993), and tau (Sontag et al. 1996). Mutations of different PPP2R2 subunits produce deleterious effects in yeast and Drosophila (Shiomi et al. 1994). Downregulation of PP2A contain-

Fig. 8 PP2A holoenzyme structure. After a complex forms between structural (A) and catalytic (C) subunits, methylestification of the catalytic unit by a 38-kDa AdoMet-dependent PP2A methyltransferase (PPMT) favors the incorporation of a regulatory unit (B). Demethylation by a 46-kDa PP2A methylesterase (PPME) destabilizes the trimeric structure (Tolstykh et al. 2000). The regulatory unit forms a ^-propeller structure. The protruding N-terminus of the regulatory unit targets the PP2A holoenzyme to intracellular domains and substrates. N-terminus variability among the multiple regulatory subunits provides spatial and temporal specificity for PP2A activity

Fig. 8 PP2A holoenzyme structure. After a complex forms between structural (A) and catalytic (C) subunits, methylestification of the catalytic unit by a 38-kDa AdoMet-dependent PP2A methyltransferase (PPMT) favors the incorporation of a regulatory unit (B). Demethylation by a 46-kDa PP2A methylesterase (PPME) destabilizes the trimeric structure (Tolstykh et al. 2000). The regulatory unit forms a ^-propeller structure. The protruding N-terminus of the regulatory unit targets the PP2A holoenzyme to intracellular domains and substrates. N-terminus variability among the multiple regulatory subunits provides spatial and temporal specificity for PP2A activity ing either PPP2R2A or PPP2R2B in cultured mammalian brain slices results in Alzheimer's-like accumulation of hyperphosphorylated tau (Sontag et al. 1999; Gong et al. 2000).

Adding to the complexity of understanding the physiological role of PPP2R2B, it, like other regulatory units, has multiple alternative splice forms. In the mouse, at least three splice forms have been examined (Schmidt et al. 2002), each with a variable first exon spliced to invariant downstream exons (our preliminary examination of human splice variants demonstrates an even greater complexity). This is of particular interest because each alternative first exon is under the control of a different promoter and encodes a different N-terminal signal. Structurally, the N-terminal portion of each regulatory subunit is exposed, with the functional consequence that this N-terminus provides the targeting information for PP2A.

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