Biology:PQBP1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Polyglutamine-binding protein 1 is a protein that in humans is encoded by the PQBP1 gene.[1][2][3]

Polyglutamine binding protein-1, which was identified as a binding protein to the polyglutamine tract sequence,[1][3] is an evolutionally conserved protein[4] expressed in various tissues including developmental[5] and adult brains[3] or mesodermal tissues.[6] In cells, PQBP1 is dominantly located in the nucleus[3][7] but also in the cytoplasm dependently on the cell type[8] and stress conditions.[9]

Function

PQBP1 is a nuclear polyglutamine-binding protein that contains a WW domain.[3][10]

The molecular roles of PQBP1 are mainly in mRNA splicing[11][12] and transcription.[7][13] PQBP1 interacts with splicing proteins[14][15][16][17] and RNA-binding proteins.[18][19] PQBP1 deficiency critically affects mRNA splicing of cell cycle and synapse related genes.[11] In addition, recent results indicated implication of PQBP1 in cytoplasmic RNA metabolism[20] and elongation of protein translation from mRNA.[21]

Clinical significance

Mutations in the PQBP1 gene, which encodes for this protein, have been known to cause X-linked intellectual disabilities (XLID), commonly referred to as Renpenning's syndrome.[22] People who suffer from these disabilities share a common set of symptoms including: microcephaly, shortened stature and impaired intellectual development.[23] There are 11 types of mutations that have been identified, but the most common being frameshift mutations.[22][24] Other syndromic XLIDs such as Golabi-Ito-Hall syndrome and non-syndromic ID patients were also associated with PQBP1 gene mutations.[25][26][27]

Mutant Ataxin-1 and Huntingtin, disease proteins of spinocerebellar ataxia type-1 and Huntington's disease respectively, interact with PQBP1 and disturbed the functions of PQBP1.[7][28] Moreover, recent investigations revealed pathological roles of PQBP1 in neurons[29] and microglia[8] under neurodegeneration of Alzheimer's disease and tauopathy. SRRM2 phosphorylation detected in neurons at the early stage of Alzheimer's disease pathology[30] leads to reduction of SRRM2, a scaffold protein for RNA metabolism related molecules in the nucleus, which causes reduction of PQBP1 in the nucleus and acquired intellectual disability.[29] PQBP1 was shown as an intracellular receptor for HIV1 in dendritic cells[31] for innate immune system. Similarly, PQBP1 functions as an intracellular receptor for tau proteins and trigger brain inflammation.[8]

Animal models

Mouse models of knockdown and conditional knockout were generated, and they showed cognitive impairment and microcephaly.[32][11] The KD mice possess a transgene expressing 498 bp double-strand RNA that is endogenously cleaved to siRNA suppressing PQBP1 efficiently, and did not show obvious developmental abnormality.[32] Another knockdown model of the gene in mouse embryo primary neurons revealed a decrease in splicing efficiency and resulted in abnormal gastrulation and neuralation patterning.[6]

Drosophila models of underexpression and overexpression were also generated.[33][34] The hypomorph Drodophila model revealed molecular function of PQBP1 in learning acquisition mediated by decreased mRNA and protein expressions of NMDA receptor subunit NR1.[33] Research indicates that in order to appropriately function, the protein must be expressed within a critical range.[35][6]

References

  1. ↑ 1.0 1.1 "Polar amino acid-rich sequences bind to polyglutamine tracts". Biochemical and Biophysical Research Communications 253 (1): 16–20. December 1998. doi:10.1006/bbrc.1998.9725. PMID 9875212. 
  2. ↑ "Novel truncating mutations in the polyglutamine tract binding protein 1 gene (PQBP1) cause Renpenning syndrome and X-linked mental retardation in another family with microcephaly". American Journal of Human Genetics 74 (4): 777–780. April 2004. doi:10.1086/383205. PMID 15024694. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival". Human Molecular Genetics 8 (6): 977–987. June 1999. doi:10.1093/hmg/8.6.977. PMID 10332029. 
  4. ↑ "PQBP-1 (Np/PQ): a polyglutamine tract-binding and nuclear inclusion-forming protein". Brain Research Bulletin 56 (3–4): 273–280. November 2001. doi:10.1016/S0361-9230(01)00579-2. PMID 11719261. 
  5. ↑ "PQBP-1 is expressed predominantly in the central nervous system during development". The European Journal of Neuroscience 22 (6): 1277–1286. September 2005. doi:10.1111/j.1460-9568.2005.04339.x. PMID 16190883. 
  6. ↑ 6.0 6.1 6.2 "The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling". Development 141 (19): 3740–3751. October 2014. doi:10.1242/dev.106658. PMID 25209246. 
  7. ↑ 7.0 7.1 7.2 "Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death". Neuron 34 (5): 701–713. May 2002. doi:10.1016/S0896-6273(02)00697-9. PMID 12062018. 
  8. ↑ 8.0 8.1 8.2 "Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation". Nature Communications 12 (1): 6565. November 2021. doi:10.1038/s41467-021-26851-2. PMID 34782623. Bibcode: 2021NatCo..12.6565J. 
  9. ↑ "The X-chromosome-linked intellectual disability protein PQBP1 is a component of neuronal RNA granules and regulates the appearance of stress granules". Human Molecular Genetics 20 (24): 4916–4931. December 2011. doi:10.1093/hmg/ddr430. PMID 21933836. 
  10. ↑ "OMIM: PQBP1 polyglutamine binding protein 1". https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300463. 
  11. ↑ 11.0 11.1 11.2 "In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells". Molecular Psychiatry 20 (4): 459–471. April 2015. doi:10.1038/mp.2014.69. PMID 25070536. 
  12. ↑ "PQBP1, an intrinsically disordered/denatured protein at the crossroad of intellectual disability and neurodegenerative diseases". Neurochemistry International 119: 17–25. October 2018. doi:10.1016/j.neuint.2017.06.005. PMID 28627366. 
  13. ↑ "Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5-15 kD". Nature Communications 5: 3822. April 2014. doi:10.1038/ncomms4822. PMID 24781215. Bibcode: 2014NatCo...5.3822M. 
  14. ↑ "Evidence that dim1 associates with proteins involved in pre-mRNA splicing, and delineation of residues essential for dim1 interactions with hnRNP F and Npw38/PQBP-1". Gene 257 (1): 33–43. October 2000. doi:10.1016/S0378-1119(00)00372-3. PMID 11054566. 
  15. ↑ "PQBP-1/Npw38, a nuclear protein binding to the polyglutamine tract, interacts with U5-15kD/dim1p via the carboxyl-terminal domain". Biochemical and Biophysical Research Communications 273 (2): 592–595. July 2000. doi:10.1006/bbrc.2000.2992. PMID 10873650. 
  16. ↑ "Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5-15 kD". Nature Communications 5 (1): 3822. April 2014. doi:10.1038/ncomms4822. PMID 24781215. Bibcode: 2014NatCo...5.3822M. 
  17. ↑ "PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth". Genes & Development 27 (6): 615–626. March 2013. doi:10.1101/gad.212308.112. PMID 23512658. 
  18. ↑ "Association of two nuclear proteins, Npw38 and NpwBP, via the interaction between the WW domain and a novel proline-rich motif containing glycine and arginine". The Journal of Biological Chemistry 274 (51): 36513–36519. December 1999. doi:10.1074/jbc.274.51.36513. PMID 10593949. 
  19. ↑ "SIPP1, a novel pre-mRNA splicing factor and interactor of protein phosphatase-1". The Biochemical Journal 378 (Pt 1): 229–238. February 2004. doi:10.1042/bj20030950. PMID 14640981. 
  20. ↑ "Common pathological mutations in PQBP1 induce nonsense-mediated mRNA decay and enhance exclusion of the mutant exon". Human Mutation 31 (1): 90–98. January 2010. doi:10.1002/humu.21146. PMID 19847789. 
  21. ↑ "PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation". Molecular Cell 81 (7): 1425–1438.e10. April 2021. doi:10.1016/j.molcel.2021.01.032. PMID 33662272. 
  22. ↑ 22.0 22.1 "Renpenning syndrome comes into focus". American Journal of Medical Genetics. Part A 134 (4): 415–421. May 2005. doi:10.1002/ajmg.a.30664. PMID 15782410. 
  23. ↑ "Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation". Nature Genetics 35 (4): 313–315. December 2003. doi:10.1038/ng1264. PMID 14634649. 
  24. ↑ "The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males". Clinical Genetics 79 (3): 225–235. March 2011. doi:10.1111/j.1399-0004.2010.01551.x. PMID 20950397. 
  25. ↑ "Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene". Journal of Medical Genetics 43 (6): e30. June 2006. doi:10.1136/jmg.2005.037556. PMID 16740914. 
  26. ↑ "Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing". The Journal of Biological Chemistry 285 (25): 19391–19401. June 2010. doi:10.1074/jbc.M109.084525. PMID 20410308. 
  27. ↑ "Molecular insights into the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1". FEBS Letters 586 (17): 2795–2799. August 2012. doi:10.1016/j.febslet.2012.03.041. PMID 22710169. 
  28. ↑ "Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington's disease". The Journal of Biological Chemistry 278 (42): 41452–41461. October 2003. doi:10.1074/jbc.M303354200. PMID 12888569. 
  29. ↑ 29.0 29.1 "The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology". Molecular Psychiatry 23 (10): 2090–2110. October 2018. doi:10.1038/s41380-018-0253-8. PMID 30283027. 
  30. ↑ "Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer's disease brain". Human Molecular Genetics 24 (2): 540–558. January 2015. doi:10.1093/hmg/ddu475. PMID 25231903. 
  31. ↑ "PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1". Cell 161 (6): 1293–1305. June 2015. doi:10.1016/j.cell.2015.04.050. PMID 26046437. 
  32. ↑ 32.0 32.1 "Knock-down of PQBP1 impairs anxiety-related cognition in mouse". Human Molecular Genetics 18 (22): 4239–4254. November 2009. doi:10.1093/hmg/ddp378. PMID 19661183. 
  33. ↑ 33.0 33.1 "Drosophila PQBP1 regulates learning acquisition at projection neurons in aversive olfactory conditioning". The Journal of Neuroscience 30 (42): 14091–14101. October 2010. doi:10.1523/JNEUROSCI.1319-10.2010. PMID 20962230. 
  34. ↑ "Expression of human PQBP-1 in Drosophila impairs long-term memory and induces abnormal courtship". FEBS Letters 580 (9): 2335–2340. April 2006. doi:10.1016/j.febslet.2006.03.056. PMID 16597440. 
  35. ↑ "A restricted level of PQBP1 is needed for the best longevity of Drosophila". Neurobiology of Aging 34 (1): 356.e11–356.e20. January 2013. doi:10.1016/j.neurobiolaging.2012.07.015. PMID 22901698. 

Further reading

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