PROLINE-RICH PROTEIN 7; PRR7

HGNC Approved Gene Symbol: PRR7

Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:177,445,994-177,456,285 (from NCBI)

▼ Description

PRR7 is a transmembrane adaptor protein that regulates signaling and apoptosis in activated T cells (Hrdinka et al., 2011) and NMDA-mediated excitotoxicity in neurons (Kravchick et al., 2016).

▼ Cloning and Expression

By database analysis, Murata et al. (2005) identified human, mouse, and rat PRR7. The deduced 274-amino acid human PRR7 protein shares at least 94% identity with its mouse and rat orthologs and has a calculated molecular mass of about 30 kD. PRR7 has a single-spanning transmembrane domain near its N terminus, followed by a large cytoplasmic domain containing proline-rich sequences and a C-terminal type I PDZ-binding motif. Immunoblot analysis detected a 37-kD protein in transfected COS-1 cell lysates. Prr7 localized in the postsynaptic density (PSD) fraction of rat forebrain. In rat brain, Prr7 expression was restricted to cerebral cortex and hippocampus. Immunoblot analysis of rat cerebral cortex and hippocampus showed that Prr7 expression was undetectable at the prenatal stage and progressively increased during maturation. In rat hippocampal neuron primary culture, Prr7 colocalized with Psd95 (DLG4; 602887) in a punctate pattern.

Hrdinka et al. (2011) reported that human PRR7 has a short N-terminal extracellular sequence, a transmembrane segment, and a cytoplasmic sequence containing several conserved binding motifs, including multiple SH2-binding and/or endocytic tyrosine-based motifs, multiple proline-rich SH3-binding motifs, group I WW domain-binding motifs, a potential submembrane palmitoylation motif, and a C-terminal class I PDZ-binding motif. Quantitative RT-PCR of human tissues showed strongest PRR7 expression in brain and moderate expression in esophagus, trachea, lung, ovary, cervix, prostate, testis, thyroid, thymus, and lymph node. The T-cell line MOLT-4 was the only human cell line that exhibited relatively high expression of PRR7. PRR7 was upregulated in phytohemagglutinin-stimulated human peripheral blood lymphocytes. In transfected Jurkat cells, PRR7 localized at the plasma membrane and to large vesicular perinuclear structures. Time-course analysis suggested that PRR7 was continuously removed from the plasma membrane by endocytosis.

Kravchick et al. (2016) found that Prr7 was highly expressed in rat forebrain and showed strong developmental regulation. Immunocytochemical analysis of rat primary hippocampal cultures revealed that endogenous Prr7 had a punctate distribution throughout synaptodendritic compartments and colocalized with synaptic markers. Western blot analysis of subcellular fractions from rat brain showed that Prr7 was markedly enriched in the PSD fraction, but was also present in purified nuclear fractions.

▼ Gene Function

Using immunoprecipitation and pull-down assays, Murata et al. (2005) found that rodent Prr7 bound to the third PDZ domain of Psd95. Prr7 also bound the NMDA receptor subunits Nr1 (GRIN1; 138249) and Nr2b (GRIN2B; 138252).

Hrdinka et al. (2011) found that overexpression of PRR7 in Jurkat cells resulted in caspase-dependent apoptosis. Mutation analysis revealed that a tyrosine-based motif surrounding tyr166 of PRR7 was essential for induction of apoptosis, and a PRR7 mutant lacking the extracellular and transmembrane domains induced the highest level of apoptosis. Amino acids 151 to 171 of PRR7 were critical for internalization of PRR7 from plasma membrane to perinuclear cytoplasmic compartments. The authors determined that the tyrosines within this conserved region were not part of tyrosine-based internalization sequences, but rather were involved in proapoptotic signaling. PRR7 expression in Jurkat cells had a dual activating/inhibitory effect, resulting in selective upregulation of JUN (165160) and CD69 (107273) and enhanced production of IL2 (147680), as well as inhibition of proximal T-cell receptor (TCR; see 186880) signaling, an attenuated calcium response, and reduced global tyrosine phosphorylation after TCR stimulation. Further analysis revealed that PRR7 was constitutively tyrosine phosphorylated and associated with SRC (190090).

Using fluorescence recovery after photobleaching, imaging, and biochemical analyses of endogenous Prr7 in rat primary hippocampal cultures, Kravchick et al. (2016) found that NMDA receptor activation caused translocation of Prr7 from synapses to nucleus. Further analysis using transfected HEK293 cells and rat cultures demonstrated that PRR7 interacted with the NMDA receptor subunit GLUN1 (GRIN1) independent of PSD95 and dissociated from NMDA receptors following neuronal activity to allow for PRR7 nuclear import. Prr7 knockdown decreased Jun abundance in primary neuronal cultures, whereas Prr7 overexpression increased Jun abundance by inhibiting Jun ubiquitination. In transfected HEK293 cells, PRR7 formed a complex with JUN and FBW7 (606278), and this complex was stabilized in the presence of all 3 components. Microarray analysis of neuronal cultures demonstrated that Prr7 mediated NMDA-dependent excitotoxicity through regulation of Jun-dependent transcription.

▼ Gene Structure

Murata et al. (2005) determined that the PRR7 gene contains 2 coding exons.

▼ Mapping

Gross (2019) mapped the PRR7 gene to chromosome 5q35.3 based on an alignment of the PRR7 sequence (GenBank BC024233) with the genomic sequence (GRCh38).