PURA , the gene encoding Pur-alpha, member of an ancient nucleic acid-binding protein family with mammalian neurological functions

Abstract

The PURA gene encodes Pur-alpha, a 322 amino acid protein with repeated nucleic acid binding domains that are highly conserved from bacteria through humans. PUR genes with a single copy of this domain have been detected so far in spirochetes and bacteroides. Lower eukaryotes possess one copy of the PUR gene, whereas chordates possess 1 to 4 PUR family members. Human PUR genes encode Pur-alpha (Pura), Pur-beta (Purb) and two forms of Pur-gamma (Purg). Pur-alpha is a protein that binds specific DNA and RNA sequence elements. Human PURA, located at chromosome band 5q31, is under complex control of three promoters. The entire protein coding sequence of PURA is contiguous within a single exon. Several studies have found that overexpression or microinjection of Pura inhibits anchorage-independent growth of oncogenically transformed cells and blocks proliferation at either G1-S or G2-M checkpoints. Effects on the cell cycle may be mediated by interaction of Pura with cellular proteins including Cyclin/Cdk complexes and the Rb tumor suppressor protein. PURA knockout mice die shortly after birth with effects on brain and hematopoietic development. In humans environmentally induced heterozygous deletions of PURA have been implicated in forms of myelodysplastic syndrome and progression to acute myelogenous leukemia. Pura plays a role in AIDS through association with the HIV-1 protein, Tat. In the brain Tat and Pura association in glial cells activates transcription and replication of JC polyomavirus, the agent causing the demyelination disease, progressive multifocal leukoencephalopathy. Tat and Pura also act to stimulate replication of the HIV-1 RNA genome. In neurons Pura accompanies mRNA transcripts to sites of translation in dendrites. Microdeletions in the PURA locus have been implicated in several neurological disorders. De novo PURA mutations have been related to a spectrum of phenotypes indicating a potential PURA syndrome. The nucleic acid, G-rich Pura binding element is amplified as expanded polynucleotide repeats in several brain diseases including fragile X syndrome and a familial form of amyotrophic lateral sclerosis/fronto-temporal dementia. Throughout evolution the Pura protein plays a critical role in survival, based on conservation of its nucleic acid binding properties. These Pura properties have been adapted in higher organisms to the as yet unfathomable development of the human brain.

PURB is a positive regulator of amino acid‐induced milk synthesis in bovine mammary epithelial cells

“…Some evidence indicates that PURB plays a critical role in gene transcription, but the reports are relatively fewer compared to many other transcriptional factors (Daniel & Johnson, ; Johnson et al, ). In the current study, we show that PURB is a positive regulator of milk protein and fat synthesis in BMECs.…”

The Lyme disease spirochete's BpuR DNA/RNA‐binding protein is differentially expressed during the mammal–tick infectious cycle, which affects translation of the SodA superoxide dismutase

“…‘PUR’ domains, such as that in BpuR, exhibit affinity to purine‐rich nucleic acid sequences (Bergemann et al , ; Graebsch et al , ; Jutras et al , ; ; Daniel and Johnson, ). The two BpuR‐binding sites that have been identified conform to that prediction: the sodA 1 and bpuR RNA probes both contain extensive stretches of purine nucleotides (Fig.…”

“…Homologues of BpuR are encoded by many other spirochetes, including members of the genera Treponema and Spirochaeta , and by some other genera, such as Bacteroides and Butyricimonas . Intriguingly, PUR domain proteins are widespread throughout eukaryotes, where they often perform critical regulatory functions through interactions with nucleic acids (Daniel and Johnson, ). Results of these and other studies on BpuR suggest that its functions are distinct from the well‐characterized bacterial RNA‐binding protein Hfq (Lybecker et al , ; Woodson et al , ).…”

“…It is a homodimer of two 122 residue polypeptides, which fold into a symmetric ‘PUR’ domain (Graebsch et al , ; ). That motif is conserved in prokaryotic and eukaryotic nucleic acid‐binding proteins, and is so‐named because PUR domain proteins exhibit high affinity for purine‐rich stretches of nucleic acids (Bergemann et al , ; Daniel and Johnson, ). BpuR was first identified as a DNA‐binding protein that functions as a co‐repressor of B. burgdorferi erp operons, enhancing the activity of the BpaB repressor protein (Burns et al , ; Jutras et al , ; ).…”

Three Individuals with PURA Syndrome in a Cohort of Patients with Neuromuscular Disease

“…Notably, PURA is known to play a crucial role in central nervous system formation and development by escorting mRNA transcripts to sites of translation in dendrites. 1,2 and present three patients with neuromuscular and ataxic features, two of them carrying novel variants.…”