Home LiteratureArticle Details
PMID: 21151134 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity.

Nature cell biology ·Vol. 13 ·No. 1 ·2011-01-00 ·Pages 30-9

Sharma M, Burré J, Südhof TC

Abstract

A neuron forms thousands of presynaptic nerve terminals on its axons, far removed from the cell body. The protein CSPα resides in presynaptic terminals, where it forms a chaperone complex with Hsc70 and SGT. Deletion of CSPα results in massive neurodegeneration that impairs survival in mice and flies. In CSPα-knockout mice, levels of presynaptic SNARE complexes and the SNARE protein SNAP-25 are reduced, suggesting that CSPα may chaperone SNARE proteins, which catalyse synaptic vesicle fusion. Here, we show that the CSPα-Hsc70-SGT complex binds directly to monomeric SNAP-25 to prevent its aggregation, enabling SNARE-complex formation. Deletion of CSPα produces an abnormal SNAP-25 conformer that inhibits SNARE-complex formation, and is subject to ubiquitylation and proteasomal degradation. Even in wild-type mouse terminals, SNAP-25 degradation is regulated by synaptic activity; this degradation is decreased by CSPα overexpression, and enhanced by CSPα deletion. Thus, SNAP-25 function is maintained during rapid SNARE cycles by equilibrium between CSPα-dependent chaperoning and ubiquitin-dependent degradation, revealing unique protein quality-control machinery within the presynaptic compartment.

MeSH Terms
Animals Animals, Newborn Brain/metabolism Cells, Cultured Female HEK293 Cells HSC70 Heat-Shock Proteins/metabolism HSP40 Heat-Shock Proteins/genetics,metabolism,physiology Humans Immunoblotting Male Membrane Proteins/genetics,metabolism,physiology Mice Mice, Knockout Mice, Transgenic Molecular Chaperones/genetics,metabolism Neurons/cytology,metabolism,physiology Proteasome Endopeptidase Complex/metabolism Protein Binding Rats Reverse Transcriptase Polymerase Chain Reaction SNARE Proteins/genetics,metabolism Synaptic Transmission/physiology Synaptosomal-Associated Protein 25/genetics,metabolism Temperature Ubiquitination alpha-Synuclein/genetics,metabolism,physiology
Chemicals
HSC70 Heat-Shock Proteins HSP40 Heat-Shock Proteins Hspa8 protein, mouse Membrane Proteins Molecular Chaperones SNARE Proteins Snap25 protein, mouse Synaptosomal-Associated Protein 25 alpha-Synuclein cysteine string protein Proteasome Endopeptidase Complex
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Sharma Manu
Department of Molecular and Cellular Physiology, Stanford University, SIM1, 265 Campus Drive, Palo Alto, CA 94304-5453, USA. [email protected]
Burré Jacqueline
Südhof Thomas C
References (45)
45 references, click to expand
  1. Cysteine string protein-alpha prevents activity-dependent degeneration in GABAergic synapses.
    J Neurosci. 2010 May 26;30(21):7377-91 PMID: 20505105
  2. Paralysis and early death in cysteine string protein mutants of Drosophila.
    Science. 1994 Feb 18;263(5149):977-80 PMID: 8310297
  3. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.
    Cell. 2005 Nov 4;123(3):383-96 PMID: 16269331
  4. Molecular chaperones in the cytosol: from nascent chain to folded protein.
    Science. 2002 Mar 8;295(5561):1852-8 PMID: 11884745
  5. CSPalpha-deficiency causes massive and rapid photoreceptor degeneration.
    Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2926-31 PMID: 16477021
  6. The DnaJ-like cysteine string protein and exocytotic neurotransmitter release.
    Trends Neurosci. 1997 May;20(5):223-7 PMID: 9141199
  7. Physiological temperatures reduce the rate of vesicle pool depletion and short-term depression via an acceleration of vesicle recruitment.
    J Neurosci. 2006 Feb 1;26(5):1366-77 PMID: 16452660
  8. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders.
    Neuromolecular Med. 2003;3(2):65-94 PMID: 12728191
  9. Presynaptic dysfunction in Drosophila csp mutants.
    Neuron. 1994 Oct;13(4):899-907 PMID: 7946336
  10. The molecular chaperone function of the secretory vesicle cysteine string proteins.
    J Biol Chem. 1997 Dec 12;272(50):31420-6 PMID: 9395474
  11. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples.
    Biotechniques. 1993 Sep;15(3):532-4, 536-7 PMID: 7692896
  12. SNAREs--engines for membrane fusion.
    Nat Rev Mol Cell Biol. 2006 Sep;7(9):631-43 PMID: 16912714
  13. Calmodulin controls synaptic strength via presynaptic activation of calmodulin kinase II.
    J Neurosci. 2010 Mar 17;30(11):4132-42 PMID: 20237283
  14. Peripheral protein quality control removes unfolded CFTR from the plasma membrane.
    Science. 2010 Aug 13;329(5993):805-10 PMID: 20595578
  15. Monitoring synaptic transmission in primary neuronal cultures using local extracellular stimulation.
    J Neurosci Methods. 2007 Mar 30;161(1):75-87 PMID: 17118459
  16. A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion.
    Cell. 1993 Nov 5;75(3):409-18 PMID: 8221884
  17. Membrane fusion.
    Nat Struct Mol Biol. 2008 Jul;15(7):658-64 PMID: 18618939
  18. Secretory pathway quality control operating in Golgi, plasmalemmal, and endosomal systems.
    Traffic. 2002 Nov;3(11):771-80 PMID: 12383343
  19. Protein quality control in the early secretory pathway.
    EMBO J. 2008 Jan 23;27(2):315-27 PMID: 18216874
  20. Think locally: control of ubiquitin-dependent protein degradation in neurons.
    EMBO Rep. 2009 Jan;10(1):44-50 PMID: 19079132
  21. Synaptic vesicle traffic: rush hour in the nerve terminal.
    J Neurochem. 1993 Jul;61(1):12-21 PMID: 8515256
  22. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro.
    Science. 2010 Sep 24;329(5999):1663-7 PMID: 20798282
  23. Cysteine string protein functions directly in regulated exocytosis.
    Mol Biol Cell. 1998 Aug;9(8):2259-67 PMID: 9693380
  24. Cysteine string protein-alpha is essential for the high calcium sensitivity of exocytosis in a vertebrate synapse.
    Eur J Neurosci. 2008 Jun;27(12):3118-31 PMID: 18598257
  25. Membrane fusion: grappling with SNARE and SM proteins.
    Science. 2009 Jan 23;323(5913):474-7 PMID: 19164740
  26. The synaptic vesicle protein CSP alpha prevents presynaptic degeneration.
    Neuron. 2004 Apr 22;42(2):237-51 PMID: 15091340
  27. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution.
    Nature. 1998 Sep 24;395(6700):347-53 PMID: 9759724
  28. Cysteine-string protein: the chaperone at the synapse.
    J Neurochem. 2000 May;74(5):1781-9 PMID: 10800920
  29. Extensive lipidation of a Torpedo cysteine string protein.
    J Biol Chem. 1994 Jul 29;269(30):19197-9 PMID: 8034679
  30. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum.
    J Neurosci. 2009 Jan 14;29(2):444-53 PMID: 19144844
  31. Conformational and temperature-sensitive stability defects of the delta F508 cystic fibrosis transmembrane conductance regulator in post-endoplasmic reticulum compartments.
    J Biol Chem. 2001 Mar 23;276(12):8942-50 PMID: 11124952
  32. Peptide binding and release by proteins implicated as catalysts of protein assembly.
    Science. 1989 Jul 28;245(4916):385-90 PMID: 2756425
  33. Synaptotagmin-1, -2, and -9: Ca(2+) sensors for fast release that specify distinct presynaptic properties in subsets of neurons.
    Neuron. 2007 May 24;54(4):567-81 PMID: 17521570
  34. A trimeric protein complex functions as a synaptic chaperone machine.
    Neuron. 2001 Sep 27;31(6):987-99 PMID: 11580898
  35. ATP-induced protein-Hsp70 complex dissociation requires K+ but not ATP hydrolysis.
    Nature. 1993 Oct 14;365(6447):664-6 PMID: 8413631
  36. Essential functions of synapsins I and II in synaptic vesicle regulation.
    Nature. 1995 Jun 8;375(6531):488-93 PMID: 7777057
  37. Pathways of chaperone-mediated protein folding in the cytosol.
    Nat Rev Mol Cell Biol. 2004 Oct;5(10):781-91 PMID: 15459659
  38. Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer's disease.
    J Neurosci. 2008 Dec 31;28(53):14392-400 PMID: 19118172
  39. Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator.
    J Biol Chem. 2002 Aug 9;277(32):28948-58 PMID: 12039948
  40. Ubiquitination in postsynaptic function and plasticity.
    Annu Rev Cell Dev Biol. 2010;26:179-210 PMID: 20604708
  41. SNAP receptors implicated in vesicle targeting and fusion.
    Nature. 1993 Mar 25;362(6418):318-24 PMID: 8455717
  42. A complexin/synaptotagmin 1 switch controls fast synaptic vesicle exocytosis.
    Cell. 2006 Sep 22;126(6):1175-87 PMID: 16990140
  43. CSPalpha: the neuroprotective J protein.
    Biochem Cell Biol. 2010 Apr;88(2):157-65 PMID: 20453918
  44. Synaptic vesicle membrane fusion complex: action of clostridial neurotoxins on assembly.
    EMBO J. 1994 Nov 1;13(21):5051-61 PMID: 7957071
  45. Specificity of Ca2+-dependent protein interactions mediated by the C2A domains of synaptotagmins.
    Biochemistry. 2000 Mar 21;39(11):2940-9 PMID: 10715114
Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb2131
Email
[email protected]
Published
2011-01-00
Epub
2010-00-12
Pages
30-9
Language
English
Region
England
NLM ID
100890575
Subset
IM
Grants
NIA NIH HHS · RC2AG036614 · United States
Howard Hughes Medical Institute · United States
Corrections
ErratumIn
-
CommentIn
PMID: 21173802
External Links
PubMed source DOI: 10.1038/ncb2131 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2