8OI8

Cryo-EM structure of ADP-bound, filamentous beta-actin harboring the R183W mutation

Summary for 8OI8

• Entry DOI: 10.2210/pdb8oi8/pdb
• Related: 8OI6
• EMDB information: 16887 16888
• Descriptor: Actin, cytoplasmic 1, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: actin filament, cytoskeletal protein, atpase, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 211220.70

Authors

Oosterheert, W.,Blanc, F.E.C.,Roy, A.,Belyy, A.,Hofnagel, O.,Hummer, G.,Bieling, P.,Raunser, S. (deposition date: 2023-03-22, release date: 2023-08-16, Last modification date: 2023-11-22)

Primary citation

Oosterheert, W.,Blanc, F.E.C.,Roy, A.,Belyy, A.,Sanders, M.B.,Hofnagel, O.,Hummer, G.,Bieling, P.,Raunser, S.
Molecular mechanisms of inorganic-phosphate release from the core and barbed end of actin filaments.
Nat.Struct.Mol.Biol., 30:1774-1785, 2023

PubMed Abstract: The release of inorganic phosphate (P) from actin filaments constitutes a key step in their regulated turnover, which is fundamental to many cellular functions. The mechanisms underlying P release from the core and barbed end of actin filaments remain unclear. Here, using human and bovine actin isoforms, we combine cryo-EM with molecular-dynamics simulations and in vitro reconstitution to demonstrate how actin releases P through a 'molecular backdoor'. While constantly open at the barbed end, the backdoor is predominantly closed in filament-core subunits and opens only transiently through concerted amino acid rearrangements. This explains why P escapes rapidly from the filament end but slowly from internal subunits. In a nemaline-myopathy-associated actin variant, the backdoor is predominantly open in filament-core subunits, resulting in accelerated P release and filaments with drastically shortened ADP-P caps. Our results provide the molecular basis for P release from actin and exemplify how a disease-linked mutation distorts the nucleotide-state distribution and atomic structure of the filament.

PubMed: 37749275
DOI: 10.1038/s41594-023-01101-9

Experimental method

ELECTRON MICROSCOPY (2.28 Å)