TY - JOUR
T1 - Bound nucleotide can control the dynamic architecture of monomeric actin
AU - Ali, Rustam
AU - Zahm, Jacob A.
AU - Rosen, Michael K.
N1 - Funding Information:
We thank L. E. Kay for providing the pulse sequences used in this work, T. Yuwen and L. E. Kay for assistance with implementation of pulse sequence and data analysis. Research was supported by the Howard Hughes Medical Institute and grants from the Welch Foundation (grant no. I-1544 to M.K.R.), the NIH (grant no. R01-GM56322 to M.K.R.) and the American Heart Association (grant no. 16POST27260081 to R.A.). NMR spectroscopy at UTSW is supported by NIH instrumentation grants nos. 1S10RR26461-1 and 1S10OD018027-01.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4
Y1 - 2022/4
N2 - Polymerization of actin into cytoskeletal filaments is coupled to its bound adenine nucleotides. The mechanism by which nucleotide modulates actin functions has not been evident from analyses of ATP- and ADP-bound crystal structures of the actin monomer. We report that NMR chemical shift differences between the two forms are globally distributed. Furthermore, microsecond–millisecond motions are spread throughout the molecule in the ATP form, but largely confined to subdomains 1 and 2, and the nucleotide binding site in the ADP form. Through these motions, the ATP- and ADP-bound forms sample different high-energy conformations. A deafness-causing, fast-nucleating actin mutant populates the high-energy conformer of ATP-actin more than the wild-type protein, suggesting that this conformer may be on the pathway to nucleation. Together, the data suggest a model in which differential sampling of a nucleation-compatible form of the actin monomer may contribute to control of actin filament dynamics by nucleotide.
AB - Polymerization of actin into cytoskeletal filaments is coupled to its bound adenine nucleotides. The mechanism by which nucleotide modulates actin functions has not been evident from analyses of ATP- and ADP-bound crystal structures of the actin monomer. We report that NMR chemical shift differences between the two forms are globally distributed. Furthermore, microsecond–millisecond motions are spread throughout the molecule in the ATP form, but largely confined to subdomains 1 and 2, and the nucleotide binding site in the ADP form. Through these motions, the ATP- and ADP-bound forms sample different high-energy conformations. A deafness-causing, fast-nucleating actin mutant populates the high-energy conformer of ATP-actin more than the wild-type protein, suggesting that this conformer may be on the pathway to nucleation. Together, the data suggest a model in which differential sampling of a nucleation-compatible form of the actin monomer may contribute to control of actin filament dynamics by nucleotide.
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U2 - 10.1038/s41594-022-00743-5
DO - 10.1038/s41594-022-00743-5
M3 - Article
C2 - 35332323
AN - SCOPUS:85127095703
SN - 1545-9993
VL - 29
SP - 320
EP - 328
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 4
ER -