CHL1 is a selective organizer of the presynaptic machinery chaperoning the SNARE complex.
Proteins constituting the presynaptic machinery of vesicle release undergo substantial conformational changes during the process of exocytosis. While changes in the conformation make proteins vulnerable to aggregation and degradation, little is known about synaptic chaperones which counteract these processes. We show that the cell adhesion molecule CHL1 directly interacts with and regulates the activity of the synaptic chaperones Hsc70, CSP and alphaSGT. CHL1, Hsc70, CSP and alphaSGT form predominantly CHL1/Hsc70/alphaSGT and CHL1/CSP complexes in synapses. Among the various complexes formed by CHL1, Hsc70, CSP and alphaSGT, SNAP25 and VAMP2 induce chaperone activity only in CHL1/Hsc70/alphaSGT and CHL1/CSP complexes, respectively, indicating a remarkable selectivity of a presynaptic chaperone activity for proteins of the exocytotic machinery. In mice with genetic ablation of CHL1, chaperone activity in synapses is reduced and the machinery for synaptic vesicle exocytosis and, in particular, the SNARE complex is unable to sustain prolonged synaptic activity. Thus, we reveal a novel role for a cell adhesion molecule in selective activation of the presynaptic chaperone machinery.
Andreyeva
Aksana
A
Zentrum für Molekulare Neurobiologie, University of Hamburg, Hamburg, Germany.
Leshchyns'ka
Iryna
I
Knepper
Michael
M
Betzel
Christian
C
Redecke
Lars
L
Sytnyk
Vladimir
V
Schachner
Melitta
M
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D011485:Protein Binding; D050600:SNARE Proteins / Q000378:metabolism*; D013312:Stress, Physiological; D013379:Substrate Specificity; D013569:Synapses / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013997:Time Factors; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C490649:Chl1 protein, mouse; D050883:HSC70 Heat-Shock Proteins; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D050600:SNARE Proteins; D050825:Synaptosomal-Associated Protein 25; D050988:Vesicle-Associated Membrane Protein 2; C088460:cysteine string protein; C494808:vesicle-associated membrane protein 2, mouse