The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
Arc N-lobe binding ligand
Functional site description:
The activity-regulated cytoskeleton-associated protein (Arc) has a retrotransposon origin and has been domesticated for synaptic functions in higher vertebrates. The Arc C-terminal domain consists of repeated 4-helix bundle domains that are homologous to the capsid domains. In the monomeric form, the first helical bundle, termed N-lobe (Arc-NL) is capable of binding peptides with variations of a PxY motif found in proteins with distinct roles in the postsynaptic densities.
ELM Description:
The motif peptide binds Arc in an unusual conformation as the middle strand of a 3-stranded β-sheet. The key structural determinants in the N-lobe are the hydrophobic pocket and a groove formed by a β-strand. The peptides bind to the Arc N-lobe by β-augmentation. A long β-strand conformation of the peptide is required as a minimal peptide of PSY fails to bind (Zhang,2015). Mutational analysis identified two key resides: Pro in P2 and Tyr in P4 (Hallin,2021). Phe can also be accepted in the P4 position (4X3I; 6TNQ). It is likely that the Pro residue in P2 is essential to keep the peptide in an extended conformation, moreover, it stabilizes binding by interacting with the aromatic ring of Tyr227 deep in the hydrophobic groove. Other stabilizing amino acids are the above Tyr/Phe which also enters a hydrophobic pocket and makes additional C–H…π interactions with Phe220 and Phe271 in Arc (6TNQ; 6TNO). P2 with Arg instead of Pro was reportedly crystallised with Arc (4X3I) although a much lower binding affinity and is unlikely to be valid for the motif. In pull-down experiments, it was shown that Pro at P3 prevents binding (Zhang,2015) as expected due to disruption of the β-strand H bonding. A similar result was obtained by the phosphomimetic mutation of Ser in P3, which seems to either radically reduce the affinity or completely abolish the interaction. However, in other experiments, the same mutation on Ser did not affect the affinity of the binding (Hallin,2021).
One of the Arc-interacting proteins (DLGP1) has a second binding motif with a Gly added in position after the Pro/Arg (6TQ0). The additional Gly residue might provide backbone flexibility that allows the alternate motif to bind with a β-bulge conformation. The requirement for backbone H bonds excludes Pro at P1, P3, and P5.
Conflicting results have been obtained for His in the P+4 Tyr/Phe position (Nielsen,2019; Zhang,2015): currently, His is included in the motif but it appears to be weaker than P+4 Tyr/Phe.
Pattern: [^P][P]G{0,1}[^P][YFH][^P]
Pattern Probability: 0.0043852
Present in taxons: Mammalia Tetrapoda
Interaction Domain:
Activity-regulated cytoskeleton-associated protein, C-terminal domain (IPR040814) This entry represents the C-terminal capsid-like domain of the Activity-regulated cytoskeleton-associated protein (Arc) (Stochiometry: 1 : 1)
o See 11 Instances for LIG_Arc_Nlobe_1
o Abstract
The Arc protein originated from Gag proteins through the Ty3/Gypsy retrotransposon family domesticated in higher vertebrates for synaptic function (Zhang,2015). The Arc C-terminal domain consists of two repeating structural elements, termed N-lobe (Arc-NL) and C-lobe (Arc-CL) (Nielsen,2019). The structure of the Arc-NL is mainly helical (59%) (Hallin,2018). The α-helices form a 4-helix bundle (Hallin,2021). Very divergent Arc-related proteins are found in other animal lineages: The Drosophila Arc C-terminal domain has the same fold as the vertebrate Arc (6TAS). However, PxY ligand motif binding does not seem to occur in the fly (Zhang,2015).
Arc likely appears in different forms providing a possibility for a wide range of functions. It can be found in free monomeric form; in association with membranes; with actin filaments; and can assemble into virus-like capsids. The function for the latter was discovered as being responsible for mRNA transfer between neurons much like in the case of HIV viruses (Nielsen,2019). Interestingly it was also shown that the motif peptide ligands (from NMDA receptors) binding to Arc proteins inhibit them from oligomerization (Nielsen,2019).
Little was known about the molecular details of Arc function until regions of partner proteins that bind the N-lobe were defined and cocrystal structures solved (Zhang,2015). The high abundance of the protein was confirmed in the brain and testis (Chen,2022). The role of Arc has been mainly investigated in glutamatergic neurons. In the synapse, Arc is a flexible hub with many postsynaptic interactors (Hallin,2021), including CAMKII (4X3I) and WAVE-1. The role of Arc is indicated in the regulation of synaptic scaling and dendritic remodelling. Furthermore, it is linked to long-term synaptic functions which are supported by the higher expression of the protein in hippocampal and cortical neurons which are responsible for memory formation (Nielsen,2019). The protein was also implicated in numerous neurological and neurobehavioral disorders such as Fragile-X syndrome or schizophrenia (Nielsen,2019).
Generally, Arc is believed to regulate diverse signaling events in postsynapsis. It was also indicated to participate in liquid-liquid phase separation (LLPS) processes (Hallin,2018). A role of Arc might be in the assistance of assembly and disassembly of protein complexes in the postsynaptic density (PSD) (Hallin,2021). The definition of the molecular context of the experimentally verified motif:domain interactions greatly varies.
While the exact role of the Arc-GKAP interaction is yet to be revealed (Hallin,2021; 6TNQ; 6TQ0), the Arc-stargazin interaction (6TNO) seems to be essential for the modulation of stargazin interaction with the PSD scaffold. A quite well-established example is Arc participating in the clathrin-mediated endocytosis machinery to promote endocytosis of AMPA receptors (Hallin,2018).
o 3 selected references:

o 8 GO-Terms:

o 11 Instances for LIG_Arc_Nlobe_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
226 230 QASAITRIPSYRYRYQRRSR TP 2 Homo sapiens (Human)
O14490 DLGAP1
483 488 VEALDLPMPGCFRMRSHSYV TP 2 Homo sapiens (Human)
O14490 DLGAP1
431 435 DPAGLLTSPKFRSRNESYMR TP 2 Homo sapiens (Human)
Q5DU25 Iqsec2
1374 1378 HPPAHKQGPKHFIFSHHPQM TP 2 Mus musculus (House mouse)
P35436 Grin2a
1170 1174 STLPMNRNPLHNEDGLPNND TP 2 Mus musculus (House mouse)
Q8R5H6 Wasf1
316 320 QSPAAGRTPVFVSPTPPPPP TP 2 Mus musculus (House mouse)
Q9D415 Dlgap1
437 441 DPAGLLTSPKFRSRNESYMR TP 2 Mus musculus (House mouse)
O88602 Cacng2
226 230 QASAITRIPSYRYRYQRRSR TP 4 Mus musculus (House mouse)
Q12879 GRIN2A
1170 1174 STLPMNRNPLHNEEGLSNND TN 1 Homo sapiens (Human)
Q00960 Grin2b
1386 1390 RVTQNPFIPTFGDDQCLLHG TP 1 Rattus norvegicus (Norway rat)
Q00959 Grin2a
1221 1225 CRSCLSNLPTYSGHFTMRSP TP 1 Rattus norvegicus (Norway rat)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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