Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy

Proceedings of the National Academy of Sciences of the United States of America
Emily E BlytheRaymond J Deshaies

Abstract

p97 is a "segregase" that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays. We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. Furthermore, we show that a p97 mutant that causes inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia in humans unfolds substrate faster, suggesting that excess activity may underlie pathogenesis. This work overcomes a significant barrier in the study of p97 and will allow the future dissection of p97 mechanism at a level of detail previously unattainable.

References

Jul 21, 1995·The Journal of Biological Chemistry·E S JohnsonA Varshavsky
Jul 3, 1997·Nature·H KondoG Warren
Sep 15, 1999·Nature·E U Weber-BanA L Horwich
Jan 5, 2000·The EMBO Journal·J S ThrowerC M Pickart
Nov 29, 2001·Proceedings of the National Academy of Sciences of the United States of America·S FangA M Weissman
Dec 12, 2001·Molecular Biology of the Cell·N W BaysR Y Hampton
May 16, 2002·The Journal of Biological Chemistry·Chang-Wei LiuPhilip J Thomas
Nov 16, 2002·Nature Structural Biology·Isabelle RouillerElizabeth M Wilson-Kubalek
Dec 31, 2002·Biochemical and Biophysical Research Communications·Qing WangChou-Chi H Li
Mar 3, 2005·Journal of Molecular Biology·Byron DeLaBarre, Axel T Brunger
Oct 21, 2005·The Journal of Biological Chemistry·Alexandra GeregaPeter Zwickl
Apr 8, 2006·The EMBO Journal·Fabienne BeuronPaul S Freemont
May 23, 2006·Molecular Cell·Byron DeLaBarreAxel T Brunger
Jan 5, 2007·Proceedings of the National Academy of Sciences of the United States of America·Valerie E PyePaul S Freemont
Mar 10, 2007·FEBS Letters·Andrea RothballerPeter Zwickl
May 11, 2007·The Journal of Biological Chemistry·Rivka L IsaacsonSteve Matthews
Mar 12, 2008·The Journal of Biological Chemistry·Louise C BriggsPaul S Freemont
Apr 29, 2008·Cellular and Molecular Life Sciences : CMLS·C Schuberth, A Buchberger
Sep 9, 2008·Cell·Gabriela AlexandruRaymond J Deshaies
Sep 29, 2009·Journal of Molecular Biology·Anne BeskowPatrick Young
Dec 17, 2009·The Journal of Cell Biology·Jeong-Sun JuConrad C Weihl
Feb 5, 2010·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Masatoshi Esaki, Teru Ogura
Apr 24, 2010·EMBO Reports·Vanesa Fernández-Sáiz, Alexander Buchberger
Jun 4, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gillian P RitsonJ Paul Taylor
Dec 2, 2010·Molecular Biology of the Cell·Shan XuMariusz Karbowski
Dec 15, 2010·Neuron·Janel O JohnsonBryan J Traynor

❮ Previous
Next ❯

Citations

Mar 9, 2018·Molecular Biology of the Cell·Edmond Y HuangJames A Olzmann
Aug 3, 2018·FEBS Letters·Debasish Kumar GhoshAkash Ranjan
Aug 16, 2018·Annual Review of Cell and Developmental Biology·Eugene OhMichael Rape
Aug 18, 2017·F1000Research·Nicholas Bodnar, Tom Rapoport
Nov 2, 2018·The Journal of Biological Chemistry·Yang WeiMatthew D Petroski
Apr 14, 2018·Annual Review of Biochemistry·Jared A M BardAndreas Martin
Dec 29, 2018·Molecular Pharmacology·Wai Kwan TangDi Xia
Sep 21, 2019·The Journal of Cell Biology·Zhihao Sun, Jeffrey L Brodsky
Feb 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·David J Sherman, Jing Li
Feb 13, 2020·Cells·Emiliano VicencioUte Woehlbier
Jun 23, 2020·Annual Review of Biochemistry·Cole S Sitron, Onn Brandman
Aug 19, 2017·The Biochemical Journal·Lasse Stach, Paul S Freemont
Mar 6, 2019·Cold Spring Harbor Perspectives in Biology·Daniel Finley, Miguel A Prado
Dec 15, 2019·Nature Communications·Yusuke SatoShuya Fukai
Apr 25, 2020·Biomolecules·Shuwen Zhang, Youdong Mao
Jul 1, 2017·Frontiers in Molecular Biosciences·Yihong YeDi Xia
Aug 29, 2019·Frontiers in Oncology·Alexey V Morozov, Vadim L Karpov
Mar 11, 2020·Nature Communications·John FieldenKristijan Ramadan
Jan 25, 2019·Communications Biology·Michal M OlszewskiAndreas Martin
Oct 28, 2019·International Journal of Molecular Sciences·Ana G PedrosaJorge E Azevedo
Jun 27, 2020·Pharmaceuticals·Hikaru TsuchiyaYasushi Saeki
Jan 12, 2020·Communications Biology·Michal M OlszewskiAndreas Martin
Mar 27, 2019·Current Opinion in Chemical Biology·Mengqi ZhongMichelle R Arkin
Apr 5, 2021·Current Opinion in Chemical Biology·Kirandeep K Deol, Eric R Strieter
Apr 17, 2021·Journal of Neuropathology and Experimental Neurology·Benjamin C CreekmoreEdward B Lee
Apr 24, 2021·Cell Chemical Biology·Predrag JevtićMichael Rapé
Mar 14, 2021·Journal of Cell Science·Sirisha MukkavalliMalavika Raman
Nov 14, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yane-Shih WangRuey-Hwa Chen
Jul 16, 2021·Nature Structural & Molecular Biology·Man PanMinglei Zhao

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.