6YTU

Atomic-resolution structure of the coiled-coil dimerisation domain of human Arc

Summary for 6YTU

• Entry DOI: 10.2210/pdb6ytu/pdb
• Descriptor: Activity-regulated cytoskeleton-associated protein, (4S)-2-METHYL-2,4-PENTANEDIOL, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: arc, oligomerisation, coiled coil, dimer, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 9205.96

Authors

Hallin, E.I.,Touma, C.,Bramham, C.R.,Kursula, P. (deposition date: 2020-04-24, release date: 2021-03-03, Last modification date: 2024-11-06)

Primary citation

Eriksen, M.S.,Nikolaienko, O.,Hallin, E.I.,Grodem, S.,Bustad, H.J.,Flydal, M.I.,Merski, I.,Hosokawa, T.,Lascu, D.,Akerkar, S.,Cuellar, J.,Chambers, J.J.,O'Connell, R.,Muruganandam, G.,Loris, R.,Touma, C.,Kanhema, T.,Hayashi, Y.,Stratton, M.M.,Valpuesta, J.M.,Kursula, P.,Martinez, A.,Bramham, C.R.
Arc self-association and formation of virus-like capsids are mediated by an N-terminal helical coil motif.
Febs J., 288:2930-2955, 2021

PubMed Abstract: Activity-regulated cytoskeleton-associated protein (Arc) is a protein interaction hub with diverse roles in intracellular neuronal signaling, and important functions in neuronal synaptic plasticity, memory, and postnatal cortical development. Arc has homology to retroviral Gag protein and is capable of self-assembly into virus-like capsids implicated in the intercellular transfer of RNA. However, the molecular basis of Arc self-association and capsid formation is largely unknown. Here, we identified a 28-amino-acid stretch in the mammalian Arc N-terminal (NT) domain that is necessary and sufficient for self-association. Within this region, we identified a 7-residue oligomerization motif, critical for the formation of virus-like capsids. Purified wild-type Arc formed capsids as shown by transmission and cryo-electron microscopy, whereas mutant Arc with disruption of the oligomerization motif formed homogenous dimers. An atomic-resolution crystal structure of the oligomerization region peptide demonstrated an antiparallel coiled-coil interface, strongly supporting NT-NT domain interactions in Arc oligomerization. The NT coil-coil interaction was also validated in live neurons using fluorescence lifetime FRET imaging, and mutation of the oligomerization motif disrupted Arc-facilitated endocytosis. Furthermore, using single-molecule photobleaching, we show that Arc mRNA greatly enhances higher-order oligomerization in a manner dependent on the oligomerization motif. In conclusion, a helical coil in the Arc NT domain supports self-association above the dimer stage, mRNA-induced oligomerization, and formation of virus-like capsids. DATABASE: The coordinates and structure factors for crystallographic analysis of the oligomerization region were deposited at the Protein Data Bank with the entry code 6YTU.

PubMed: 33175445
DOI: 10.1111/febs.15618

Experimental method

X-RAY DIFFRACTION (0.95 Å)