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Article

Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes

1
Biodesign Center for Applied Structural Discovery, School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
3
Eyring Materials Center, Arizona State University, Tempe, AZ 85287, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Dmitry B. Zorov
Int. J. Mol. Sci. 2021, 22(15), 8079; https://doi.org/10.3390/ijms22158079
Received: 2 July 2021 / Revised: 22 July 2021 / Accepted: 25 July 2021 / Published: 28 July 2021
(This article belongs to the Section Biochemistry)
IBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-length p97R155H with its p47 cofactor and first visualized their structures using single-particle cryo-EM. More than one-third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N-domains of the p97R155H mutant all show up configurations in ADP- or ATPγS-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97R155H ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97R155H. View Full-Text
Keywords: p97 ATPase; p97R155H mutation; p47 cofactor; arginine finger; IBMPFD; single-particle cryo-EM p97 ATPase; p97R155H mutation; p47 cofactor; arginine finger; IBMPFD; single-particle cryo-EM
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MDPI and ACS Style

Nandi, P.; Li, S.; Columbres, R.C.A.; Wang, F.; Williams, D.R.; Poh, Y.-P.; Chou, T.-F.; Chiu, P.-L. Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes. Int. J. Mol. Sci. 2021, 22, 8079. https://doi.org/10.3390/ijms22158079

AMA Style

Nandi P, Li S, Columbres RCA, Wang F, Williams DR, Poh Y-P, Chou T-F, Chiu P-L. Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes. International Journal of Molecular Sciences. 2021; 22(15):8079. https://doi.org/10.3390/ijms22158079

Chicago/Turabian Style

Nandi, Purbasha, Shan Li, Rod C.A. Columbres, Feng Wang, Dewight R. Williams, Yu-Ping Poh, Tsui-Fen Chou, and Po-Lin Chiu. 2021. "Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes" International Journal of Molecular Sciences 22, no. 15: 8079. https://doi.org/10.3390/ijms22158079

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