User:Andrea Foote/Sandbox 1: Difference between revisions

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== Introduction ==

'''Purine-rich element binding protein alpha (Purα)''' is a transcription factor with a molecular weight of ~35 kDa encoded by the PURA gene. It possesses ATP-independent dsDNA unwinding activity, and is known to bind sequence-specific purine-rich regions of ssDNA and ssRNA, recognizing GGN motifs. Purα is a member of the PUR family of proteins, which includes Purβ and two isoforms of Purγ. In its functional dimeric form Purα is known to repress expression of smooth muscle alpha actin (SMαA) encoded by the ''Acta2'' gene. It is also known to be involved in DNA replication and cell cycle regulation as well as mRNA translation. It plays a crucial role in nervous system development, and ~~mutations in Purα have~~ been implicated in two neurological diseases: PURA syndrome and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) (see Disease section).<ref>PMID:26744780</ref>

'''Purine-rich element binding protein alpha (Purα)''' is a transcription factor with a molecular weight of ~35 kDa encoded by the PURA gene. It possesses ATP-independent dsDNA unwinding activity, and is known to bind sequence-specific purine-rich regions of ssDNA and ssRNA, recognizing GGN motifs. Purα is a member of the PUR family of proteins, which includes Purβ and two isoforms of Purγ. In its functional dimeric form Purα is known to repress expression of smooth muscle alpha actin (SMαA) encoded by the ''Acta2'' gene. It is also known to be involved in DNA replication and cell cycle regulation as well as mRNA translation. It plays a crucial role in nervous system development, and has been implicated in two neurological diseases: PURA syndrome and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) (see Disease section).<ref>PMID:26744780</ref>

[[Image:180503 PurA dimer.jpg|thumb|center|700px| Artist representation of a Purα homodimer (linkers between repeats I-II and III (red) were drawn in PowerPoint and are NOT to scale). NOTE: This is NOT a verified model, but a rough placement to show all three repeats together. It is not known what the orientation of these domains are relative to one another. (Repeat I-II ([[5fgp]]): purple (I) and orange (II), repeat III ([[5fgo]]): cyan).]]

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== Function ==

High-affinity nucleic acid-binding function is dependent on Purα dimerization. Purα forms homodimers in addition to heterodimers with Purβ. PurA is known to repress various genes including

<scene name='78/786627/5fgp_57and145/1'>Two aromatic residues</scene>, Y57 (repeat I) and F145 (repeat II) ~~have been implicated in~~ the DNA unwinding activity of ~~PurA~~.<ref>PMID:26744780</ref>

<scene name='78/786627/5fgp_57and145/1'>Two aromatic residues spatially conserved on PUR repeats I and II</scene>, Y57 (repeat I) and F145 (repeat II), located on the solvent-exposed surface of the beta-sheets, contribute to the DNA unwinding activity of Purα through base stacking interactions with DNA bases.<ref>PMID:26744780</ref> PUR repeat III also has an aromatic residue at this location (Y219) that could undergo base-stacking interactions with DNA, however Weber, et al. observed negligible unwinding activity in this repeat.<ref>PMID:26744780</ref> Furthermore, repeat III was shown to bind DNA with significantly less affinity than repeat I-II.

== Development ==

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== Disease ==

Mutations in the ''PURA'' gene resulting in haploinsufficiency ~~of Purα~~ are known to cause the neurological disease PURA syndrome. PURA syndrome appears early in development, , with patients exhibiting severe developmental delay, seizures, feeding difficulty, of severe intellectual disabilities, movements, vision, hypotonia, premature telarche, . This disease has no cure, and life expectancy is .<ref>PMID:29097605</ref>. Purα knock-out mice exhibit similar neurological symptoms such as severe tremor developing at about postnatal week two, and feeding difficulties. These mice die after approximately one month. Heterozygous mice display less severe symptoms including seizures upon handling. <ref>PMID:25342064</ref>

Mutations in the ''PURA'' gene resulting in haploinsufficiency are known to cause the neurological disease PURA syndrome. PURA syndrome appears early in development, , with patients exhibiting severe developmental delay, seizures, feeding difficulty, of severe intellectual disabilities, movements, vision, hypotonia, premature telarche, . This disease has no cure, and life expectancy is .<ref>PMID:29097605</ref>. Purα knock-out mice exhibit similar neurological symptoms such as severe tremor developing at about postnatal week two, and feeding difficulties. These mice die after approximately one month. Heterozygous mice display less severe symptoms including seizures upon handling. <ref>PMID:25342064</ref>

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is another disease associated with abnormal activity of Purα. Normally between __ and __ copies of __ , however in greater than __ copies can result in ___ causing delayed-onset neurological problems. FXTAS generally develops in middle age, and is characterized by tremor, ataxia, and ___.

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 == Introduction ==
-'''Purine-rich element binding protein alpha (Purα)'''  is a transcription factor with a molecular weight of ~35 kDa encoded by the PURA gene. It possesses ATP-independent dsDNA unwinding activity, and is known to bind sequence-specific purine-rich regions of ssDNA and ssRNA, recognizing GGN motifs. Purα is a member of the PUR family of proteins, which includes Purβ and two isoforms of Purγ. In its functional dimeric form Purα is known to repress expression of smooth muscle alpha actin (SMαA) encoded by the ''Acta2'' gene. It is also known to be involved in DNA replication and cell cycle regulation as well as mRNA translation. It plays a crucial role in nervous system development, and mutations in Purα have been implicated in two neurological diseases: PURA syndrome and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) (see Disease section).<ref>PMID:26744780</ref>
+'''Purine-rich element binding protein alpha (Purα)'''  is a transcription factor with a molecular weight of ~35 kDa encoded by the PURA gene. It possesses ATP-independent dsDNA unwinding activity, and is known to bind sequence-specific purine-rich regions of ssDNA and ssRNA, recognizing GGN motifs. Purα is a member of the PUR family of proteins, which includes Purβ and two isoforms of Purγ. In its functional dimeric form Purα is known to repress expression of smooth muscle alpha actin (SMαA) encoded by the ''Acta2'' gene. It is also known to be involved in DNA replication and cell cycle regulation as well as mRNA translation. It plays a crucial role in nervous system development, and has been implicated in two neurological diseases: PURA syndrome and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) (see Disease section).<ref>PMID:26744780</ref>
 [[Image:180503 PurA dimer.jpg|thumb|center|700px| Artist representation of a Purα homodimer (linkers between repeats I-II and III (red) were drawn in PowerPoint and are NOT to scale). NOTE: This is NOT a verified model, but a rough placement to show all three repeats together. It is not known what the orientation of these domains are relative to one another.  (Repeat I-II ([[5fgp]]): purple (I) and orange (II), repeat III ([[5fgo]]): cyan).]]
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 == Function ==
 High-affinity nucleic acid-binding function is dependent on Purα dimerization. Purα forms homodimers in addition to heterodimers with Purβ. PurA is known to repress various genes including
-<scene name='78/786627/5fgp_57and145/1'>Two aromatic residues</scene>, Y57 (repeat I) and F145 (repeat II) have been implicated in the DNA unwinding activity of PurA.<ref>PMID:26744780</ref>
+<scene name='78/786627/5fgp_57and145/1'>Two aromatic residues spatially conserved on PUR repeats I and II</scene>, Y57 (repeat I) and F145 (repeat II), located on the solvent-exposed surface of the beta-sheets, contribute to the DNA unwinding activity of Purα through base stacking interactions with DNA bases.<ref>PMID:26744780</ref> PUR repeat III also has an aromatic residue at this location (Y219) that could undergo base-stacking interactions with DNA, however Weber, et al. observed negligible unwinding activity in this repeat.<ref>PMID:26744780</ref> Furthermore, repeat III was shown to bind DNA with significantly less affinity than repeat I-II.
 == Development ==
@@ Line 26: / Line 26: @@
 == Disease ==
-Mutations in the ''PURA'' gene resulting in haploinsufficiency of Purα are known to cause the neurological disease PURA syndrome. PURA syndrome appears early in development, , with patients exhibiting severe developmental delay, seizures, feeding difficulty,  of severe intellectual disabilities, movements, vision,  hypotonia, premature telarche, . This disease has no cure, and life expectancy is .<ref>PMID:29097605</ref>. Purα knock-out mice exhibit similar neurological symptoms such as severe tremor developing at about postnatal week two, and feeding difficulties. These mice die after approximately one month. Heterozygous mice display less severe symptoms including seizures upon handling. <ref>PMID:25342064</ref>
+Mutations in the ''PURA'' gene resulting in haploinsufficiency are known to cause the neurological disease PURA syndrome. PURA syndrome appears early in development, , with patients exhibiting severe developmental delay, seizures, feeding difficulty,  of severe intellectual disabilities, movements, vision,  hypotonia, premature telarche, . This disease has no cure, and life expectancy is .<ref>PMID:29097605</ref>. Purα knock-out mice exhibit similar neurological symptoms such as severe tremor developing at about postnatal week two, and feeding difficulties. These mice die after approximately one month. Heterozygous mice display less severe symptoms including seizures upon handling. <ref>PMID:25342064</ref>
 Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is another disease associated with abnormal activity of Purα. Normally between __ and __ copies of __ , however in greater than __ copies can result in ___ causing delayed-onset neurological problems. FXTAS generally develops in middle age, and is characterized by tremor, ataxia, and ___.