4X3H

CRYSTAL STRUCTURE OF ARC N-LOBE COMPLEXED WITH STARGAZIN PEPTIDE

Summary for 4X3H

• Entry DOI: 10.2210/pdb4x3h/pdb
• Related: 4X3I 4X3X
• Descriptor: Activity-regulated cytoskeleton-associated protein, VOLTAGE-DEPENDENT CALCIUM CHANNEL GAMMA-2 SUBUNIT (3 entities in total)
• Functional Keywords: endocytosis mediator, signaling protein
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: Q63053
• Total number of polymer chains: 2
• Total formula weight: 10622.80

Authors

zhang, W.,ward, m.,leahy, d.,worley, p. (deposition date: 2014-11-30, release date: 2015-06-03, Last modification date: 2024-02-28)

Primary citation

Zhang, W.,Wu, J.,Ward, M.D.,Yang, S.,Chuang, Y.A.,Xiao, M.,Li, R.,Leahy, D.J.,Worley, P.F.
Structural basis of arc binding to synaptic proteins: implications for cognitive disease.
Neuron, 86:490-500, 2015

PubMed Abstract: Arc is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. We report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was "domesticated" in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides and is essential for Arc's synaptic function. A consensus sequence for Arc binding identifies several additional partners that include genes implicated in schizophrenia. Arc N-lobe binding is inhibited by small chemicals suggesting Arc's synaptic action may be druggable. These studies reveal the remarkable evolutionary origin of Arc and provide a structural basis for understanding Arc's contribution to neural plasticity and disease.

PubMed: 25864631
DOI: 10.1016/j.neuron.2015.03.030

Experimental method

X-RAY DIFFRACTION (2.401 Å)