TY - JOUR
T1 - Palmitoylation and Membrane Binding of Arc/Arg3.1
T2 - A Potential Role in Synaptic Depression
AU - Barylko, Barbara
AU - Wilkerson, Julia R.
AU - Cavalier, Sheridan H.
AU - Binns, Derk D.
AU - James, Nicholas G.
AU - Jameson, David M.
AU - Huber, Kimberly M.
AU - Albanesi, Joseph P.
N1 - Funding Information:
*E-mail: Joseph.Albanesi@UTSouthwestern.edu. Telephone: 214-645-6119. Fax: 214-645-6124. ORCID Joseph P. Albanesi: 0000-0002-6864-8140 Author Contributions D.M.J., K.M.H., and J.P.A. designed the experiments and oversaw their execution. Experiments were performed by B.B., J.R.W., S.H.C., N.G.J., and D.D.B. Funding This research was supported by National Institutes of Health Grants HD052731 (K.M.H.) and MH110223 (J.P.A. and K.M.H.). Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2018/2/6
Y1 - 2018/2/6
N2 - Activity-regulated cytoskeletal-associated protein (Arc, also known as activity-regulated gene 3.1 or Arg3.1) is induced in neurons in response to salient experience and neural activity and is necessary for activity-induced forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), cellular substrates of learning and memory. The best-characterized function of Arc is enhancement of the endocytic internalization of AMPA receptors in dendritic spines, a process associated with LTD. Arc has also been implicated in the proteolytic processing of amyloid precursor protein on the surface of endosomes. To mediate these activities, Arc must associate with cellular membranes, but it is unclear whether Arc binds directly to the lipid bilayer or requires protein-protein interactions for membrane recruitment. In this study, we show that Arc associates with pure phospholipid vesicles in vitro and undergoes palmitoylation in neurons, a modification that allows it to insert directly into the hydrophobic core of the bilayer. The palmitoylated cysteines are clustered in a motif, 94CLCRC98, located in the N-terminal half of the protein, which has not yet been structurally characterized. Expression of Arc with three mutated cysteines in that motif cannot support synaptic depression induced by the activity-dependent transcription factor, MEF2 (myocyte enhancer factor 2), in contrast to wild-type Arc. Thus, it appears that palmitoylation regulates at least a subset of Arc functions in synaptic plasticity.
AB - Activity-regulated cytoskeletal-associated protein (Arc, also known as activity-regulated gene 3.1 or Arg3.1) is induced in neurons in response to salient experience and neural activity and is necessary for activity-induced forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), cellular substrates of learning and memory. The best-characterized function of Arc is enhancement of the endocytic internalization of AMPA receptors in dendritic spines, a process associated with LTD. Arc has also been implicated in the proteolytic processing of amyloid precursor protein on the surface of endosomes. To mediate these activities, Arc must associate with cellular membranes, but it is unclear whether Arc binds directly to the lipid bilayer or requires protein-protein interactions for membrane recruitment. In this study, we show that Arc associates with pure phospholipid vesicles in vitro and undergoes palmitoylation in neurons, a modification that allows it to insert directly into the hydrophobic core of the bilayer. The palmitoylated cysteines are clustered in a motif, 94CLCRC98, located in the N-terminal half of the protein, which has not yet been structurally characterized. Expression of Arc with three mutated cysteines in that motif cannot support synaptic depression induced by the activity-dependent transcription factor, MEF2 (myocyte enhancer factor 2), in contrast to wild-type Arc. Thus, it appears that palmitoylation regulates at least a subset of Arc functions in synaptic plasticity.
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U2 - 10.1021/acs.biochem.7b00959
DO - 10.1021/acs.biochem.7b00959
M3 - Article
C2 - 29264923
AN - SCOPUS:85041480633
SN - 0006-2960
VL - 57
SP - 520
EP - 524
JO - Biochemistry
JF - Biochemistry
IS - 5
ER -