PACSIN, a brain protein that is upregulated upon differentiation into neuronal cells

Plomann, Markus; Lange, Rita; Vopper, Gaby; Cremer, Harold; Heinlein, Uwe A.O.; Baldwin, Stanley A.; Leitges, Michael; Cramer, Matthias; Paulsson, Mats; Barthels, Dagmar

doi:10.1046/j.1432-1327.1998.2560201.x

Cited by 75 publications

(91 citation statements)

References 49 publications

(59 reference statements)

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“…This suggests that PACSIN1 may stabilize or modulate the conformation of the amino terminus of huntingtin. Both N17 and PACSIN1 are substrates for CK2 (12,17). Therefore, the effect of the CK2 inhibitors on the conformation of the exon1 sensor may not only be due to posttranslational modification of N17 but also to that of PACSIN1.…”

Section: Measuring the Conformation Of The Amino Terminus Within Thementioning

confidence: 99%

“…PACSIN1 is a predominantly cytoplasmic neuronal protein that has functions in NMDA receptor recycling (18,19), actin/microtubule reorganization (20), and neuronal spine formation (21). Both N17 and PACSIN1 are substrates of casein kinase 2 (CK2) (12,17).Because both of the flanking regions to the polyglutamine tract are critical in mediating the toxicity of the mutant huntingtin protein in mammalian and yeast models (22), we wanted to determine whether the two domains could be interacting with each other in 3D space using the polyglutamine tract as a flexible region. To test this hypothesis, we developed a Förster resonance energy transfer (FRET) sensor with donor and acceptor fluorophores at the amino and carboxyl-termini of huntingtin fragments, respectively.…”

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confidence: 99%

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confidence: 99%

“…Similar to the N17 domain, interacting proteins within this polyproline region have been found to affect mutant huntingtin toxicity (16). Protein kinase C and casein kinase 2 substrate in neurons (PACSIN1), or syndapin 1, binds directly to the polyproline domain (17). This interaction is enhanced in the presence of expanded polyglutamine (18).…”

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confidence: 99%

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Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Caron

Desmond

Xia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

149

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Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion within the huntingtin gene that encodes a polymorphic glutamine tract at the amino terminus of the huntingtin protein. HD is one of nine polyglutamine expansion diseases. The clinical threshold of polyglutamine expansion for HD is near 37 repeats, but the mechanism of this pathogenic length is poorly understood. Using Förster resonance energy transfer, we describe an intramolecular proximity between the N17 domain and the downstream polyproline region that flanks the polyglutamine tract of huntingtin. Our data support the hypothesis that the polyglutamine tract can act as a flexible domain, allowing the flanking domains to come into close spatial proximity. This flexibility is impaired with expanded polyglutamine tracts, and we can detect changes in huntingtin conformation at the pathogenic threshold for HD. Altering the structure of N17, either via phosphomimicry or with small molecules, also affects the proximity between the flanking domains. The structural capacity of N17 to fold back toward distal regions within huntingtin requires an interacting protein, protein kinase C and casein kinase 2 substrate in neurons 1 (PACSIN1). This protein has the ability to bind both N17 and the polyproline region, stabilizing the interaction between these two domains. We also developed an antibody-based FRET assay that can detect conformational changes within endogenous huntingtin in wild-type versus HD fibroblasts. Therefore, we hypothesize that wild-type length polyglutamine tracts within huntingtin can form a flexible domain that is essential for proper functional intramolecular proximity, conformations, and dynamics.polyglutamine diseases | conformational switching | FLIM-FRET | neurodegeneration | fluorescence lifetime imaging microscopy H untington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat within the huntingtin (HTT) gene (1). The pathogenic threshold of CAG expansion is ∼37 repeats, with increased repeats leading to an earlier age-onset of HD (2-4). This CAG mutation results in an expanded polyglutamine tract in the amino terminus of the gene's protein product, huntingtin (1). To date, no phenotypes at the level of huntingtin molecular biology or animal models can be attributed to polyglutamine lengths near the human pathogenic disease threshold (5).Polyglutamine or glutamine-rich domains are also found in transcription factors such as the Sp-family and cAMP response element-binding protein (CREB) and are defined as proteinprotein interaction motifs used to scaffold and regulate transcription by RNA polymerase II (6, 7). In the transducin-like enhancer of split (TLE) corepressor proteins, the glutamine-rich domains are thought to allow dimerization (8). However, the role of polyglutamine in proteins such as huntingtin may be distinct from that of a protein-protein interaction or dimerization domain.The polyglutamine tract of huntingtin is flanked on...

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Section: Measuring the Conformation Of The Amino Terminus Within Thementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Caron

Desmond

Xia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

129

149

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“…Pacsin1, also known as Syndapin1, is an evolutionarily conserved, brain-specific F-BAR (Fer-Cip4-Bin/Amphiphysin/Rvs) and SH3 (Src homology 3)-domain-containing protein (23,24). The SH3 domain of Pacsin1 binds to the proline-rich regions of several other proteins including dynamin1, N-WASP (neuronal Wiskott-Aldrich syndrome protein), and Synaptojanin1 (25) while the F-BAR domain is implicated in sensing and/or inducing membrane curvature (26).…”

Section: Resultsmentioning

confidence: 99%

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

Strochlic

Concilio

Viaud

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic transmission is mediated by a complex set of molecular events that must be coordinated in time and space. While many proteins that function at the synapse have been identified, the signaling pathways regulating these molecules are poorly understood. Pak5 (p21-activated kinase 5) is a brain-specific isoform of the group II Pak kinases whose substrates and roles within the central nervous system are largely unknown. To gain insight into the physiological roles of Pak5, we engineered a Pak5 mutant to selectively radiolabel its substrates in murine brain extract. Using this approach, we identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. These results implicate Pak5 in Pacsin1-and Synaptojanin1-mediated synaptic vesicle trafficking and may partially account for the cognitive and behavioral deficits observed in group II Pak-deficient mice.

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Involvement of PCH family proteins in cytokinesis and actin distribution

Lippincott

2000

Microsc. Res. Tech.

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PACSIN, a brain protein that is upregulated upon differentiation into neuronal cells

Cited by 75 publications

References 49 publications

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin

Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking

Involvement of PCH family proteins in cytokinesis and actin distribution

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