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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Review Article

Insights into the Design of p97-targeting Small Molecules from Structural Studies on p97 Functional Mechanism

Author(s): Xin Sui, Man Pan and Yi-Ming Li*

Volume 27, Issue 2, 2020

Page: [298 - 316] Pages: 19

DOI: 10.2174/0929867326666191004162411

Price: $65


p97, also known as valosin-containing protein or CDC48, is a member of the AAA+ protein family that is highly conserved in eukaryotes. It binds to various cofactors in the body to perform its protein-unfolding function and participates in DNA repair, degradation of subcellular membrane proteins, and protein quality control pathways, among other processes. Its malfunction can lead to many diseases, such as inclusion body myopathy, associated with Paget’s disease of bone and/or frontotemporal dementia, amyotrophic lateral sclerosis disease, and others. In recent years, many small-molecule inhibitors have been deployed against p97, including bis (diethyldithiocarbamate)- copper and CB-5083, which entered the first phase of clinical tests but failed. One bottleneck in the design of p97 drugs is that its molecular mechanism remains unclear. This paper summarizes recent studies on the molecular mechanisms of p97, which may lead to insight into how the next generation of small molecules targeting p97 can be designed.

Keywords: p97/VCP/CDC48, AAA+ ATPase, molecular mechanism, structure, cofactor, inhibitor.

Rabouille, C.; Levine, T.P.; Peters, J.M.; Warren, G. An NSF-like ATPase, p97, and NSF mediate cisternal regrowth from mitotic Golgi fragments. Cell, 1995, 82(6), 905-914.
[] [PMID: 7553851]
Peters, J.M.; Walsh, M.J.; Franke, W.W. An abundant and ubiquitous homo-oligomeric ring-shaped ATPase particle related to the putative vesicle fusion proteins Sec18p and NSF. EMBO J., 1990, 9(6), 1757-1767.
[] [PMID: 2140770]
Ramanathan, H.N.; Ye, Y. The p97 ATPase associates with EEA1 to regulate the size of early endosomes. Cell Res., 2012, 22(2), 346-359.
[] [PMID: 21556036]
Xu, S.; Peng, G.; Wang, Y.; Fang, S.; Karbowski, M. The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol. Biol. Cell, 2011, 22(3), 291-300.
[] [PMID: 21118995]
Llinàs-Arias, P.; Rosselló-Tortella, M.; López-Serra, P.; Pérez-Salvia, M.; Setién, F.; Marin, S.; Muñoz, J.P.; Junza, A.; Capellades, J.; Calleja-Cervantes, M.E.; Ferreira, H.J.; de Moura, M.C.; Srbic, M.; Martínez-Cardús, A.; de la Torre, C.; Villanueva, A.; Cascante, M.; Yanes, O.; Zorzano, A.; Moutinho, C.; Esteller, M. Epigenetic loss of the endoplasmic reticulum-associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming. JCI Insight, 2019, 5(8), 125888
[] [PMID: 30843871]
Lan, B.; Chai, S.; Wang, P.; Wang, K. VCP/p97/Cdc48, a linking of protein homeostasis and cancer therapy. Curr. Mol. Med., 2017, 17(9), 608-618.
[] [PMID: 29521227]
Ye, Y.; Meyer, H.H.; Rapoport, T.A. Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J. Cell Biol., 2003, 162(1), 71-84.
[] [PMID: 12847084]
Banerjee, S.; Bartesaghi, A.; Merk, A.; Rao, P.; Bulfer, S.L.; Yan, Y.; Green, N.; Mroczkowski, B.; Neitz, R.J.; Wipf, P.; Falconieri, V.; Deshaies, R.J.; Milne, J.L.S.; Huryn, D.; Arkin, M.; Subramaniam, S. 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science, 2016, 351(6275), 871-875.
[] [PMID: 26822609]
Li, G.; Zhao, G.; Schindelin, H.; Lennarz, W.J. Tyrosine phosphorylation of ATPase p97 regulates its activity during ERAD. Biochem. Biophys. Res. Commun., 2008, 375(2), 247-251.
[] [PMID: 18706391]
Ewens, C.A.; Kloppsteck, P.; Förster, A.; Zhang, X.; Freemont, P.S. Structural and functional implications of phosphorylation and acetylation in the regulation of the AAA+ protein p97. Biochem. Cell Biol., 2010, 88(1), 41-48.
[] [PMID: 20130678]
Niwa, H.; Ewens, C.A.; Tsang, C.; Yeung, H.O.; Zhang, X.; Freemont, P.S. The role of the N-domain in the ATPase activity of the mammalian AAA ATPase p97/VCP. J. Biol. Chem., 2012, 287(11), 8561-8570.
[] [PMID: 22270372]
Blythe, E.E.; Olson, K.C.; Chau, V.; Deshaies, R.J. Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP center dot NPLOC4 center dot UFD1L is enhanced by a mutation that causes multisystem proteinopathy. Proc. Natl. Acad. Sci. USA, 2017, 114(22), E4380-E4388.
[] [PMID: 28512218]
Bodnar, N.O.; Rapoport, T.A. Molecular mechanism of substrate processing by the Cdc48 ATPase complex. Cell, 2017, 169(4), 722-735, e9.
[] [PMID: 28475898]
Song, C.; Wang, Q.; Li, C.C.H. ATPase activity of p97-valosin-containing protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J. Biol. Chem., 2003, 278(6), 3648-3655.
[] [PMID: 12446676]
Wang, Q.; Song, C.; Li, C.C.H. Hexamerization of p97-VCP is promoted by ATP binding to the D1 domain and required for ATPase and biological activities. Biochem. Biophys. Res. Commun., 2003, 300(2), 253-260.
[] [PMID: 12504076]
Mouysset, J.; Deichsel, A.; Moser, S.; Hoege, C.; Hyman, A.A.; Gartner, A.; Hoppe, T. Cell cycle progression requires the CDC-48UFD-1/NPL-4 complex for efficient DNA replication. Proc. Natl. Acad. Sci. USA, 2008, 105(35), 12879-12884.
[] [PMID: 18728180]
Franz, A.; Orth, M.; Pirson, P.A.; Sonneville, R.; Blow, J.J.; Gartner, A.; Stemmann, O.; Hoppe, T. CDC-48/p97 coordinates CDT-1 degradation with GINS chromatin dissociation to ensure faithful DNA replication. Mol. Cell, 2011, 44(1), 85-96.
[] [PMID: 21981920]
Maric, M.; Maculins, T.; De Piccoli, G.; Labib, K. Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication. Science, 2014, 346(6208), 1253596
[] [PMID: 25342810]
Yamanaka, S.; Zhang, X.Y.; Maeda, M.; Miura, K.; Wang, S.; Farese, R.V. Jr.; Iwao, H.; Innerarity, T.L. Essential role of NAT1/p97/DAP5 in embryonic differentiation and the retinoic acid pathway. EMBO J., 2000, 19(20), 5533-5541.
[] [PMID: 11032820]
Mehta, S.G.; Khare, M.; Ramani, R.; Watts, G.D.J.; Simon, M.; Osann, K.E.; Donkervoort, S.; Dec, E.; Nalbandian, A.; Platt, J.; Pasquali, M.; Wang, A.; Mozaffar, T.; Smith, C.D.; Kimonis, V.E. Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia. Clin. Genet., 2013, 83(5), 422-431.
[] [PMID: 22909335]
Johnson, J.O.; Mandrioli, J.; Benatar, M.; Abramzon, Y.; Van Deerlin, V.M.; Trojanowski, J.Q.; Gibbs, J.R.; Brunetti, M.; Gronka, S.; Wuu, J.; Ding, J.; McCluskey, L.; Martinez-Lage, M.; Falcone, D.; Hernandez, D.G.; Arepalli, S.; Chong, S.; Schymick, J.C.; Rothstein, J.; Landi, F.; Wang, Y.D.; Calvo, A.; Mora, G.; Sabatelli, M.; Monsurrò, M.R.; Battistini, S.; Salvi, F.; Spataro, R.; Sola, P.; Borghero, G.; Galassi, G.; Scholz, S.W.; Taylor, J.P.; Restagno, G.; Chiò, A.; Traynor, B.J.; Consortium, I. ITALSGEN Consortium. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron, 2010, 68(5), 857-864.
[] [PMID: 21145000]
Ozsoy, A.Z.; Cayli, S.; Sahin, C.; Ocakli, S.; Sanci, T.O.; Ilhan, D.B. Altered expression of p97/Valosin containing protein and impaired autophagy in preeclamptic human placenta. Placenta, 2018, 67, 45-53.
[] [PMID: 29941173]
Valle, C.W.; Min, T.; Bodas, M.; Mazur, S.; Begum, S.; Tang, D.; Vij, N. Critical role of VCP/p97 in the pathogenesis and progression of non-small cell lung carcinoma. PLoS One, 2011, 6(12), e29073
[] [PMID: 22216170]
Auner, H.W.; Moody, A.M.; Ward, T.H.; Kraus, M.; Milan, E.; May, P.; Chaidos, A.; Driessen, C.; Cenci, S.; Dazzi, F.; Rahemtulla, A.; Apperley, J.F.; Karadimitris, A.; Dillon, N. Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells. PLoS One, 2013, 8(9), e74415
[] [PMID: 24069311]
Anderson, D.J.; Le Moigne, R.; Djakovic, S.; Kumar, B.; Rice, J.; Wong, S.; Wang, J.; Yao, B.; Valle, E.; Kiss von Soly, S.; Madriaga, A.; Soriano, F.; Menon, M.K.; Wu, Z.Y.; Kampmann, M.; Chen, Y.; Weissman, J.S.; Aftab, B.T.; Yakes, F.M.; Shawver, L.; Zhou, H.J.; Wustrow, D.; Rolfe, M. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell, 2015, 28(5), 653-665.
[] [PMID: 26555175]
van Well, E.M.; Bader, V.; Patra, M.; Sánchez-Vicente, A.; Meschede, J.; Furthmann, N.; Schnack, C.; Blusch, A.; Longworth, J.; Petrasch-Parwez, E.; Mori, K.; Arzberger, T.; Trümbach, D.; Angersbach, L.; Showkat, C.; Sehr, D.A.; Berlemann, L.A.; Goldmann, P.; Clement, A.M.; Behl, C.; Woerner, A.C.; Saft, C.; Wurst, W.; Haass, C.; Ellrichmann, G.; Gold, R.; Dittmar, G.; Hipp, M.S.; Hartl, F.U.; Tatzelt, J.; Winklhofer, K.F. A protein quality control pathway regulated by linear ubiquitination. EMBO J., 2019, 38(9), e100730
[PMID: 30886048]
Meyer, H.; Weihl, C.C. The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J. Cell Sci., 2014, 127(Pt 18), 3877-3883.
[] [PMID: 25146396]
Bebeacua, C.; Förster, A.; McKeown, C.; Meyer, H.H.; Zhang, X.; Freemont, P.S. Distinct conformations of the protein complex p97-Ufd1-Npl4 revealed by electron cryomicroscopy. Proc. Natl. Acad. Sci. USA, 2012, 109(4), 1098-1103.
[] [PMID: 22232657]
Rose, T.M.; Plowman, G.D.; Teplow, D.B.; Dreyer, W.J.; Hellström, K.E.; Brown, J.P. Primary structure of the human melanoma-associated antigen p97 (melanotransferrin) deduced from the mRNA sequence. Proc. Natl. Acad. Sci. USA, 1986, 83(5), 1261-1265.
[] [PMID: 2419904]
Zhang, L.; Ashendel, C.L.; Becker, G.W.; Morré, D.J. Isolation and characterization of the principal ATPase associated with transitional endoplasmic reticulum of rat liver. J. Cell Biol., 1994, 127(6 Pt 2), 1871-1883.
[] [PMID: 7806566]
Huyton, T.; Pye, V.E.; Briggs, L.C.; Flynn, T.C.; Beuron, F.; Kondo, H.; Ma, J.; Zhang, X.; Freemont, P.S. The crystal structure of murine p97/VCP at 3.6A. J. Struct. Biol., 2003, 144(3), 337-348.
[] [PMID: 14643202]
Davies, J.M.; Brunger, A.T.; Weis, W.I. Improved structures of full-length p97, an AAA ATPase: implications for mechanisms of nucleotide-dependent conformational change. Structure, 2008, 16(5), 715-726.
[] [PMID: 18462676]
Tang, W.K.; Li, D.; Li, C.C.; Esser, L.; Dai, R.; Guo, L.; Xia, D. A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants. EMBO J., 2010, 29(13), 2217-2229.
[] [PMID: 20512113]
Tang, W.K.; Xia, D. Structural and functional deviations in disease-associated p97 mutants. J. Struct. Biol., 2012, 179(2), 83-92.
[] [PMID: 22579784]
Tang, W.K.; Xia, D. Altered intersubunit communication is the molecular basis for functional defects of pathogenic p97 mutants. J. Biol. Chem., 2013, 288(51), 36624-36635.
[] [PMID: 24196964]
Beuron, F.; Dreveny, I.; Yuan, X.; Pye, V.E.; McKeown, C.; Briggs, L.C.; Cliff, M.J.; Kaneko, Y.; Wallis, R.; Isaacson, R.L.; Ladbury, J.E.; Matthews, S.J.; Kondo, H.; Zhang, X.; Freemont, P.S. Conformational changes in the AAA ATPase p97-p47 adaptor complex. EMBO J., 2006, 25(9), 1967-1976.
[] [PMID: 16601695]
Huang, R.; Ripstein, Z.A.; Rubinstein, J.L.; Kay, L.E. Cooperative subunit dynamics modulate p97 function. Proc. Natl. Acad. Sci. USA, 2019, 116(1), 158-167.
[] [PMID: 30584095]
Rouiller, I.; Butel, V.M.; Latterich, M.; Milligan, R.A.; Wilson-Kubalek, E.M. A major conformational change in p97 AAA ATPase upon ATP binding. Mol. Cell, 2000, 6(6), 1485-1490.
[] [PMID: 11163220]
Zhang, X.; Shaw, A.; Bates, P.A.; Newman, R.H.; Gowen, B.; Orlova, E.; Gorman, M.A.; Kondo, H.; Dokurno, P.; Lally, J.; Leonard, G.; Meyer, H.; van Heel, M.; Freemont, P.S. Structure of the AAA ATPase p97. Mol. Cell, 2000, 6(6), 1473-1484.
[] [PMID: 11163219]
Ripstein, Z.A.; Huang, R.; Augustyniak, R.; Kay, L.E.; Rubinstein, J.L. Structure of a AAA+ unfoldase in the process of unfolding substrate. eLife, 2017, 6, pii: e25754
[] [PMID: 28390173]
Schuller, J.M.; Beck, F.; Lössl, P.; Heck, A.J.R.; Förster, F. Nucleotide-dependent conformational changes of the AAA+ ATPase p97 revisited. FEBS Lett., 2016, 590(5), 595-604.
[] [PMID: 26849035]
Rothballer, A.; Tzvetkov, N.; Zwickl, P. Mutations in p97/VCP induce unfolding activity. FEBS Lett., 2007, 581(6), 1197-1201.
[] [PMID: 17346713]
Tang, W.K.; Zhang, T.; Ye, Y.; Xia, D. Structural basis for nucleotide-modulated p97 association with the ER membrane. Cell Discov., 2017, 3, 17045.
[] [PMID: 29238611]
Schuetz, A.K.; Kay, L.E. A Dynamic molecular basis for malfunction in disease mutants of p97/VCP. eLife, 2016, 5, pii: e20143
[] [PMID: 27828775]
Nishikori, S.; Esaki, M.; Yamanaka, K.; Sugimoto, S.; Ogura, T. Positive cooperativity of the p97 AAA ATPase is critical for essential functions. J. Biol. Chem., 2011, 286(18), 15815-15820.
[] [PMID: 21454554]
Chou, T.F.; Bulfer, S.L.; Weihl, C.C.; Li, K.; Lis, L.G.; Walters, M.A.; Schoenen, F.J.; Lin, H.J.; Deshaies, R.J.; Arkin, M.R. Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains. J. Mol. Biol., 2014, 426(15), 2886-2899.
[] [PMID: 24878061]
Li, G.; Huang, C.; Zhao, G.; Lennarz, W.J. Interprotomer motion-transmission mechanism for the hexameric AAA ATPase p97. Proc. Natl. Acad. Sci. USA, 2012, 109(10), 3737-3741.
[] [PMID: 22355145]
DeLaBarre, B.; Brunger, A.T. Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat. Struct. Biol., 2003, 10(10), 856-863.
[] [PMID: 12949490]
Tang, W.K.; Xia, D. Role of the D1-D2 linker of human VCP/p97 in the asymmetry and ATPase activity of the D1-domain. Sci. Rep., 2016, 6, 20037.
[] [PMID: 26818443]
Huang, C.; Li, G.; Lennarz, W.J. Dynamic flexibility of the ATPase p97 is important for its interprotomer motion transmission. Proc. Natl. Acad. Sci. USA, 2012, 109(25), 9792-9797.
[] [PMID: 22675116]
Buchberger, A.; Schindelin, H.; Hänzelmann, P. Control of p97 function by cofactor binding. FEBS Lett., 2015, 589(19 Pt A), 2578-2589.
[] [PMID: 26320413]
Sasagawa, Y.; Yamanaka, K.; Saito-Sasagawa, Y.; Ogura, T. Caenorhabditis elegans UBX cofactors for CDC-48/p97 control spermatogenesis. Genes Cells, 2010, 15(12), 1201-1215.
[] [PMID: 20977550]
Böhm, S.; Lamberti, G.; Fernández-Sáiz, V.; Stapf, C.; Buchberger, A. Cellular functions of Ufd2 and Ufd3 in proteasomal protein degradation depend on Cdc48 binding. Mol. Cell. Biol., 2011, 31(7), 1528-1539.
[] [PMID: 21282470]
Schaeffer, V.; Akutsu, M.; Olma, M.H.; Gomes, L.C.; Kawasaki, M.; Dikic, I. Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling. Mol. Cell, 2014, 54(3), 349-361.
[] [PMID: 24726327]
Yang, F.C.; Lin, Y.H.; Chen, W.H.; Huang, J.Y.; Chang, H.Y.; Su, S.H.; Wang, H.T.; Chiang, C.Y.; Hsu, P.H.; Tsai, M.D.; Tan, B.C.; Lee, S.C. Interaction between salt-inducible kinase 2 (SIK2) and p97/valosin-containing protein (VCP) regulates endoplasmic reticulum (ER)-associated protein degradation in mammalian cells. J. Biol. Chem., 2013, 288(47), 33861-33872.
[] [PMID: 24129571]
Elia, A.E.; Boardman, A.P.; Wang, D.C.; Huttlin, E.L.; Everley, R.A.; Dephoure, N.; Zhou, C.; Koren, I.; Gygi, S.P.; Elledge, S.J. Quantitative proteomic atlas of ubiquitination and acetylation in the DNA damage response. Mol. Cell, 2015, 59(5), 867-881.
[] [PMID: 26051181]
Wu, Q.; Cheng, Z.; Zhu, J.; Xu, W.; Peng, X.; Chen, C.; Li, W.; Wang, F.; Cao, L.; Yi, X.; Wu, Z.; Li, J.; Fan, P. Suberoylanilide hydroxamic acid treatment reveals crosstalks among proteome, ubiquitylome and acetylome in non-small cell lung cancer A549 cell line. Sci. Rep., 2015, 5, 9520.
[] [PMID: 25825284]
Matic, I.; van Hagen, M.; Schimmel, J.; Macek, B.; Ogg, S.C.; Tatham, M.H.; Hay, R.T.; Lamond, A.I.; Mann, M.; Vertegaal, A.C.O. In vivo identification of human small ubiquitin-like modifier polymerization sites by high accuracy mass spectrometry and an in vitro to in vivo strategy. Mol. Cell. Proteomics, 2008, 7(1), 132-144.
[] [PMID: 17938407]
Hendriks, I.A.; Lyon, D.; Young, C.; Jensen, L.J.; Vertegaal, A.C.; Nielsen, M.L. Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol., 2017, 24(3), 325-336.
[] [PMID: 28112733]
Hänzelmann, P.; Schindelin, H. The interplay of cofactor interactions and post-translational modifications in the regulation of the AAA+ ATPase p97. Front. Mol. Biosci., 2017, 4, 21.
[] [PMID: 28451587]
Tonddast-Navaei, S.; Stan, G. Mechanism of transient binding and release of substrate protein during the allosteric cycle of the p97 nanomachine. J. Am. Chem. Soc., 2013, 135(39), 14627-14636.
[] [PMID: 24007343]
DeLaBarre, B.; Christianson, J.C.; Kopito, R.R.; Brunger, A.T. Central pore residues mediate the p97/VCP activity required for ERAD. Mol. Cell, 2006, 22(4), 451-462.
[] [PMID: 16713576]
Meyer, H.J.; Rape, M. Enhanced protein degradation by branched ubiquitin chains. Cell, 2014, 157(4), 910-921.
[] [PMID: 24813613]
Stach, L.; Freemont, P.S. The AAA+ ATPase p97, a cellular multitool. Biochem. J., 2017, 474(17), 2953-2976.
[] [PMID: 28819009]
Xia, D.; Tang, W.K.; Ye, Y. Structure and function of the AAA+ ATPase p97/Cdc48p. Gene, 2016, 583(1), 64-77.
[] [PMID: 26945625]
Ernst, R.; Mueller, B.; Ploegh, H.L.; Schlieker, C. The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER. Mol. Cell, 2009, 36(1), 28-38.
[] [PMID: 19818707]
Sasset, L.; Petris, G.; Cesaratto, F.; Burrone, O.R. The VCP/p97 and YOD1 proteins have different substrate-dependent activities in endoplasmic reticulum-associated degradation (ERAD). J. Biol. Chem., 2015, 290(47), 28175-28188.
[] [PMID: 26463207]
Cesaratto, F.; Sasset, L.; Myers, M.P.; Re, A.; Petris, G.; Burrone, O.R. BiP/GRP78 mediates ERAD targeting of proteins produced by membrane-bound ribosomes stalled at the STOP-Codon. J. Mol. Biol., 2019, 431(2), 123-141.
[] [PMID: 30367842]
Papadopoulos, C.; Kirchner, P.; Bug, M.; Grum, D.; Koerver, L.; Schulze, N.; Poehler, R.; Dressler, A.; Fengler, S.; Arhzaouy, K.; Lux, V.; Ehrmann, M.; Weihl, C.C.; Meyer, H. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J., 2017, 36(2), 135-150.
[] [PMID: 27753622]
Zhang, X.; Zhang, H.; Wang, Y. Phosphorylation regulates VCIP135 function in Golgi membrane fusion during the cell cycle. J. Cell Sci., 2014, 127(Pt 1), 172-181.
[] [PMID: 24163436]
Uchiyama, K.; Jokitalo, E.; Kano, F.; Murata, M.; Zhang, X.; Canas, B.; Newman, R.; Rabouille, C.; Pappin, D.; Freemont, P.; Kondo, H. VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo. J. Cell Biol., 2002, 159(5), 855-866.
[] [PMID: 12473691]
He, J.; Zhu, Q.; Wani, G.; Sharma, N.; Wani, A.A. Valosin-containing Protein (VCP)/p97 Segregase Mediates Proteolytic Processing of Cockayne Syndrome Group B (CSB) in Damaged Chromatin. J. Biol. Chem., 2016, 291(14), 7396-7408.
[] [PMID: 26826127]
Li, Z.H.; Wang, Y.; Xu, M.; Jiang, T. Crystal structures of the UBX domain of human UBXD7 and its complex with p97 ATPase. Biochem. Biophys. Res. Commun., 2017, 486(1), 94-100.
[] [PMID: 28274878]
Alexandru, G.; Graumann, J.; Smith, G.T.; Kolawa, N.J.; Fang, R.; Deshaies, R.J. UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover. Cell, 2008, 134(5), 804-816.
[] [PMID: 18775313]
Lee, J.N.; Kim, H.; Yao, H.; Chen, Y.; Weng, K.; Ye, J. Identification of Ubxd8 protein as a sensor for unsaturated fatty acids and regulator of triglyceride synthesis. Proc. Natl. Acad. Sci. USA, 2010, 107(50), 21424-21429.
[] [PMID: 21115839]
Olzmann, J.A.; Richter, C.M.; Kopito, R.R. Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. Proc. Natl. Acad. Sci. USA, 2013, 110(4), 1345-1350.
[] [PMID: 23297223]
Hänzelmann, P.; Schindelin, H. Characterization of an additional binding surface on the p97 N-Terminal domain involved in bipartite cofactor interactions. Structure, 2016, 24(1), 140-147.
[] [PMID: 26712280]
Zhang, X.; Gui, L.; Zhang, X.; Bulfer, S.L.; Sanghez, V.; Wong, D.E.; Lee, Y.; Lehmann, L.; Lee, J.S.; Shih, P.Y.; Lin, H.J.; Iacovino, M.; Weihl, C.C.; Arkin, M.R.; Wang, Y.; Chou, T.F. Altered cofactor regulation with disease-associated p97/VCP mutations. Proc. Natl. Acad. Sci. USA, 2015, 112(14), E1705-E1714.
[] [PMID: 25775548]
Park, E.S.; Yoo, Y.J.; Elangovan, M. The opposite role of two UBA-UBX containing proteins, p47 and SAKS1 in the degradation of a single ERAD substrate, α-TCR. Mol. Cell. Biochem., 2017, 425(1-2), 37-45.
[] [PMID: 27785701]
Song, J.; Park, J.K.; Lee, J.J.; Choi, Y.S.; Ryu, K.S.; Kim, J.H.; Kim, E.; Lee, K.J.; Jeon, Y.H.; Kim, E.E. Structure and interaction of ubiquitin-associated domain of human Fas-associated factor 1. Protein Sci., 2009, 18(11), 2265-2276.
[] [PMID: 19722279]
Ewens, C.A.; Panico, S.; Kloppsteck, P.; McKeown, C.; Ebong, I.O.; Robinson, C.; Zhang, X.; Freemont, P.S. The p97-FAF1 protein complex reveals a common mode of p97 adaptor binding. J. Biol. Chem., 2014, 289(17), 12077-12084.
[] [PMID: 24619421]
Xie, F.; Jin, K.; Shao, L.; Fan, Y.; Tu, Y.; Li, Y.; Yang, B.; van Dam, H.; Ten Dijke, P.; Weng, H.; Dooley, S.; Wang, S.; Jia, J.; Jin, J.; Zhou, F.; Zhang, L. FAF1 phosphorylation by AKT accumulates TGF-β type II receptor and drives breast cancer metastasis. Nat. Commun., 2017, 8, 15021.
[] [PMID: 28443643]
LaLonde, D.P.; Bretscher, A. The UBX protein SAKS1 negatively regulates endoplasmic reticulum-associated degradation and p97-dependent degradation. J. Biol. Chem., 2011, 286(6), 4892-4901.
[] [PMID: 21135095]
Madsen, L.; Andersen, K.M.; Prag, S.; Moos, T.; Semple, C.A.; Seeger, M.; Hartmann-Petersen, R. Ubxd1 is a novel co-factor of the human p97 ATPase. Int. J. Biochem. Cell Biol., 2008, 40(12), 2927-2942.
[] [PMID: 18656546]
Fang, S.; Ferrone, M.; Yang, C.; Jensen, J.P.; Tiwari, S.; Weissman, A.M. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA, 2001, 98(25), 14422-14427.
[] [PMID: 11724934]
Zhang, T.; Xu, Y.; Liu, Y.; Ye, Y. gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum. Mol. Biol. Cell, 2015, 26(24), 4438-4450.
[] [PMID: 26424800]
Orme, C.M.; Bogan, J.S. The ubiquitin regulatory X (UBX) domain-containing protein TUG regulates the p97 ATPase and resides at the endoplasmic reticulum-golgi intermediate compartment. J. Biol. Chem., 2012, 287(9), 6679-6692.
[] [PMID: 22207755]
Laço, M.N.; Cortes, L.; Travis, S.M.; Paulson, H.L.; Rego, A.C. Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3. PLoS One, 2012, 7(9), e43563
[] [PMID: 22970133]
Li, X.; Liu, H.; Fischhaber, P.L.; Tang, T.S. Toward therapeutic targets for SCA3: Insight into the role of Machado-Joseph disease protein ataxin-3 in misfolded proteins clearance. Prog. Neurobiol., 2015, 132, 34-58.
[] [PMID: 26123252]
Sirisaengtaksin, N.; Gireud, M.; Yan, Q.; Kubota, Y.; Meza, D.; Waymire, J.C.; Zage, P.E.; Bean, A.J. UBE4B protein couples ubiquitination and sorting machineries to enable epidermal growth factor receptor (EGFR) degradation. J. Biol. Chem., 2014, 289(5), 3026-3039.
[] [PMID: 24344129]
Ackermann, L.; Schell, M.; Pokrzywa, W.; Kevei, É.; Gartner, A.; Schumacher, B.; Hoppe, T. E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis. Nat. Struct. Mol. Biol., 2016, 23(11), 995-1002.
[] [PMID: 27669035]
Stieglitz, B.; Rana, R.R.; Koliopoulos, M.G.; Morris-Davies, A.C.; Schaeffer, V.; Christodoulou, E.; Howell, S.; Brown, N.R.; Dikic, I.; Rittinger, K. Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature, 2013, 503(7476), 422-426.
[] [PMID: 24141947]
Bodnar, N.O.; Kim, K.H.; Ji, Z.; Wales, T.E.; Svetlov, V.; Nudler, E.; Engen, J.R.; Walz, T.; Rapoport, T.A. Structure of the Cdc48 ATPase with its ubiquitin-binding cofactor Ufd1-Npl4. Nat. Struct. Mol. Biol., 2018, 25(7), 616-622.
[] [PMID: 29967539]
Maric, M.; Mukherjee, P.; Tatham, M.H.; Hay, R.; Labib, K. Ufd1-Npl4 recruit Cdc48 for disassembly of ubiquitylated CMG helicase at the end of chromosome replication. Cell Rep., 2017, 18(13), 3033-3042.
[] [PMID: 28355556]
Hülsmann, J.; Kravic, B.; Weith, M.; Gstaiger, M.; Aebersold, R.; Collins, B.C.; Meyer, H. AP-SWATH reveals direct involvement of VCP/p97 in integrated stress response signaling through facilitating CReP/PPP1R15B degradation. Mol. Cell. Proteomics, 2018, 17(7), 1295-1307.
[] [PMID: 29599191]
Rageul, J.; Park, J.J.; Jo, U.; Weinheimer, A.S.; Vu, T.T.M.; Kim, H. Conditional degradation of SDE2 by the Arg/N-End rule pathway regulates stress response at replication forks. Nucleic Acids Res., 2019, 47(8), 3996-4010.
[] [PMID: 30698750]
Le, L.T.; Kang, W.; Kim, J.Y.; Le, O.T.; Lee, S.Y.; Yang, J.K. Structural Details of Ufd1 Binding to p97 and Their Functional Implications in ER-Associated Degradation. PLoS One, 2016, 11(9), e0163394
[] [PMID: 27684549]
Isaacson, R.L.; Pye, V.E.; Simpson, P.; Meyer, H.H.; Zhang, X.; Freemont, P.S.; Matthews, S. Detailed structural insights into the p97-Npl4-Ufd1 interface. J. Biol. Chem., 2007, 282(29), 21361-21369.
[] [PMID: 17491009]
Kondo, H.; Rabouille, C.; Newman, R.; Levine, T.P.; Pappin, D.; Freemont, P.; Warren, G. p47 is a cofactor for p97-mediated membrane fusion. Nature, 1997, 388(6637), 75-78.
[] [PMID: 9214505]
Dreveny, I.; Kondo, H.; Uchiyama, K.; Shaw, A.; Zhang, X.; Freemont, P.S. Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47. EMBO J., 2004, 23(5), 1030-1039.
[] [PMID: 14988733]
Meyer, H.H. Golgi reassembly after mitosis: the AAA family meets the ubiquitin family. Biochim. Biophys. Acta, 2005, 1744(2), 108-119.
[] [PMID: 15878210]
Uchiyama, K.; Kondo, H. p97/p47-Mediated biogenesis of Golgi and ER. J. Biochem., 2005, 137(2), 115-119.
[] [PMID: 15749824]
Shibata, Y.; Oyama, M.; Kozuka-Hata, H.; Han, X.; Tanaka, Y.; Gohda, J.; Inoue, J. p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO. Nat. Commun., 2012, 3, 1061.
[] [PMID: 22990857]
Yeung, H.O.; Kloppsteck, P.; Niwa, H.; Isaacson, R.L.; Matthews, S.; Zhang, X.; Freemont, P.S. Insights into adaptor binding to the AAA protein p97. Biochem. Soc. Trans., 2008, 36(Pt 1), 62-67.
[] [PMID: 18208387]
Bruderer, R.M.; Brasseur, C.; Meyer, H.H. The AAA ATPase p97/VCP interacts with its alternative co-factors, Ufd1-Npl4 and p47, through a common bipartite binding mechanism. J. Biol. Chem., 2004, 279(48), 49609-49616.
[] [PMID: 15371428]
Hurley, J.H.; Lee, S.; Prag, G. Ubiquitin-binding domains. Biochem. J., 2006, 399(3), 361-372.
[] [PMID: 17034365]
Kloppsteck, P.; Ewens, C.A.; Förster, A.; Zhang, X.; Freemont, P.S. Regulation of p97 in the ubiquitin-proteasome system by the UBX protein-family. Biochim. Biophys. Acta, 2012, 1823(1), 125-129.
[] [PMID: 21963883]
Bandau, S.; Knebel, A.; Gage, Z.O.; Wood, N.T.; Alexandru, G. UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation. BMC Biol., 2012, 10, 36.
[] [PMID: 22537386]
Cross, B.C.; McKibbin, C.; Callan, A.C.; Roboti, P.; Piacenti, M.; Rabu, C.; Wilson, C.M.; Whitehead, R.; Flitsch, S.L.; Pool, M.R.; High, S.; Swanton, E. Eeyarestatin I inhibits Sec61-mediated protein translocation at the endoplasmic reticulum. J. Cell Sci., 2009, 122(Pt 23), 4393-4400.
[] [PMID: 19903691]
Fiebiger, E.; Hirsch, C.; Vyas, J.M.; Gordon, E.; Ploegh, H.L.; Tortorella, D. Dissection of the dislocation pathway for type I membrane proteins with a new small molecule inhibitor, eeyarestatin. Mol. Biol. Cell, 2004, 15(4), 1635-1646.
[] [PMID: 14767067]
Wang, Q.; Li, L.; Ye, Y. Inhibition of p97-dependent protein degradation by Eeyarestatin I. J. Biol. Chem., 2008, 283(12), 7445-7454.
[] [PMID: 18199748]
Wang, Q.; Shinkre, B.A.; Lee, J.G.; Weniger, M.A.; Liu, Y.; Chen, W.; Wiestner, A.; Trenkle, W.C.; Ye, Y. The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group. PLoS One, 2010, 5(11), e15479
[] [PMID: 21124757]
Chou, T.F.; Brown, S.J.; Minond, D.; Nordin, B.E.; Li, K.; Jones, A.C.; Chase, P.; Porubsky, P.R.; Stoltz, B.M.; Schoenen, F.J.; Patricelli, M.P.; Hodder, P.; Rosen, H.; Deshaies, R.J. Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc. Natl. Acad. Sci. USA, 2011, 108(12), 4834-4839.
[] [PMID: 21383145]
Walworth, K.; Bodas, M.; Campbell, R.J.; Swanson, D.; Sharma, A.; Vij, N. Dendrimer-Based Selective Proteostasis-Inhibition Strategy to Control NSCLC Growth and Progression. PLoS One, 2016, 11(7), e0158507
[] [PMID: 27434122]
Chou, T.F.; Li, K.; Frankowski, K.J.; Schoenen, F.J.; Deshaies, R.J. Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase. ChemMedChem, 2013, 8(2), 297-312.
[] [PMID: 23316025]
Zhou, H.J.; Wang, J.; Yao, B.; Wong, S.; Djakovic, S.; Kumar, B.; Rice, J.; Valle, E.; Soriano, F.; Menon, M.K.; Madriaga, A.; Kiss von Soly, S.; Kumar, A.; Parlati, F.; Yakes, F.M.; Shawver, L.; Le Moigne, R.; Anderson, D.J.; Rolfe, M.; Wustrow, D. Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083). J. Med. Chem., 2015, 58(24), 9480-9497.
[] [PMID: 26565666]
Bursavich, M.G.; Parker, D.P.; Willardsen, J.A.; Gao, Z.H.; Davis, T.; Ostanin, K.; Robinson, R.; Peterson, A.; Cimbora, D.M.; Zhu, J.F.; Richards, B. 2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97). Bioorg. Med. Chem. Lett., 2010, 20(5), 1677-1679.
[] [PMID: 20137940]
Magnaghi, P.; D’Alessio, R.; Valsasina, B.; Avanzi, N.; Rizzi, S.; Asa, D.; Gasparri, F.; Cozzi, L.; Cucchi, U.; Orrenius, C.; Polucci, P.; Ballinari, D.; Perrera, C.; Leone, A.; Cervi, G.; Casale, E.; Xiao, Y.; Wong, C.; Anderson, D.J.; Galvani, A.; Donati, D.; O’Brien, T.; Jackson, P.K.; Isacchi, A. Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat. Chem. Biol., 2013, 9(9), 548-556.
[] [PMID: 23892893]
Cervi, G.; Magnaghi, P.; Asa, D.; Avanzi, N.; Badari, A.; Borghi, D.; Caruso, M.; Cirla, A.; Cozzi, L.; Felder, E.; Galvani, A.; Gasparri, F.; Lomolino, A.; Magnuson, S.; Malgesini, B.; Motto, I.; Pasi, M.; Rizzi, S.; Salom, B.; Sorrentino, G.; Troiani, S.; Valsasina, B.; O’Brien, T.; Isacchi, A.; Donati, D.; D’Alessio, R. Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors. J. Med. Chem., 2014, 57(24), 10443-10454.
[] [PMID: 25474526]
Sasazawa, Y.; Kanagaki, S.; Tashiro, E.; Nogawa, T.; Muroi, M.; Kondoh, Y.; Osada, H.; Imoto, M. Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein. ACS Chem. Biol., 2012, 7(5), 892-900.
[] [PMID: 22360440]
Alverez, C.; Arkin, M.R.; Bulfer, S.L.; Colombo, R.; Kovaliov, M.; LaPorte, M.G.; Lim, C.; Liang, M.; Moore, W.J.; Neitz, R.J.; Yan, Y.; Yue, Z.; Huryn, D.M.; Wipf, P. Structure-activity study of bioisosteric trifluoromethyl and pentafluorosulfanyl indole inhibitors of the AAA ATPase p97. ACS Med. Chem. Lett., 2015, 6(12), 1225-1230.
[] [PMID: 26713109]
Alverez, C.; Bulfer, S.L.; Chakrasali, R.; Chimenti, M.S.; Deshaies, R.J.; Green, N.; Kelly, M.; LaPorte, M.G.; Lewis, T.S.; Liang, M.; Moore, W.J.; Neitz, R.J.; Peshkov, V.A.; Walters, M.A.; Zhang, F.; Arkin, M.R.; Wipf, P.; Huryn, D.M. Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway. ACS Med. Chem. Lett., 2015, 7(2), 182-187.
[] [PMID: 26985295]
Lyupina, Y.V.; Erokhov, P.A.; Kravchuk, O.I.; Finoshin, A.D.; Abaturova, S.B.; Orlova, O.V.; Beljelarskaya, S.N.; Kostyuchenko, M.V.; Mikhailov, V.S. Essential function of VCP/p97 in infection cycle of the nucleopolyhedrovirus AcMNPV in Spodoptera frugiperda Sf9 cells. Virus Res., 2018, 253, 68-76.
[] [PMID: 29890203]
Her, N.G.; Toth, J.I.; Ma, C.T.; Wei, Y.; Motamedchaboki, K.; Sergienko, E.; Petroski, M.D. p97 composition changes caused by allosteric inhibition are suppressed by an on-target mechanism that increases the enzyme’s ATPase activity. Cell Chem. Biol., 2016, 23(4), 517-528.
[] [PMID: 27105284]
Iljin, K.; Ketola, K.; Vainio, P.; Halonen, P.; Kohonen, P.; Fey, V.; Grafström, R.C.; Perälä, M.; Kallioniemi, O. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin. Cancer Res., 2009, 15(19), 6070-6078.
[] [PMID: 19789329]
Cvek, B. Nonprofit drugs as the salvation of the world’s healthcare systems: the case of Antabuse (disulfiram). Drug Discov. Today, 2012, 17(9-10), 409-412.
[] [PMID: 22192884]
Allensworth, J.L.; Evans, M.K.; Bertucci, F.; Aldrich, A.J.; Festa, R.A.; Finetti, P.; Ueno, N.T.; Safi, R.; McDonnell, D.P.; Thiele, D.J.; Van Laere, S.; Devi, G.R. Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol. Oncol., 2015, 9(6), 1155-1168.
[] [PMID: 25769405]
Skrott, Z.; Mistrik, M.; Andersen, K.K.; Friis, S.; Majera, D.; Gursky, J.; Ozdian, T.; Bartkova, J.; Turi, Z.; Moudry, P.; Kraus, M.; Michalova, M.; Vaclavkova, J.; Dzubak, P.; Vrobel, I.; Pouckova, P.; Sedlacek, J.; Miklovicova, A.; Kutt, A.; Li, J.; Mattova, J.; Driessen, C.; Dou, Q.P.; Olsen, J.; Hajduch, M.; Cvek, B.; Deshaies, R.J.; Bartek, J. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature, 2017, 552(7684), 194-199.
[] [PMID: 29211715]
Huang, E.Y.; To, M.; Tran, E.; Dionisio, L.T.A.; Cho, H.J.; Baney, K.L.M.; Pataki, C.I.; Olzmann, J.A. A VCP inhibitor substrate trapping approach (VISTA) enables proteomic profiling of endogenous ERAD substrates. Mol. Biol. Cell, 2018, 29(9), 1021-1030.
[] [PMID: 29514927]
Bastola, P.; Minn, K.; Chien, J. Heterozygous mutations in p97 and resistance to p97 inhibitors. bioRxiv, 2018.
Wei, Y.; Toth, J.I.; Blanco, G.A.; Bobkov, A.A.; Petroski, M.D. Adapted ATPase domain communication overcomes the cytotoxicity of p97 inhibitors. J. Biol. Chem., 2018, 293(52), 20169-20180.
[] [PMID: 30381397]
Vekaria, P.H.; Kumar, A.; Subramaniam, D.; Dunavin, N.; Vallurupalli, A.; Schoenen, F.; Ganguly, S.; Anant, S.; McGuirk, J.P.; Jensen, R.A.; Rao, R. Functional cooperativity of p97 and histone deacetylase 6 in mediating DNA repair in mantle cell lymphoma cells. Leukemia, 2019, 33(7), 1675-1686.
[] [PMID: 30664664]
Tang, W.K.; Odzorig, T.; Jin, W.; Xia, D. Structural basis of p97 inhibition by the site-selective anticancer compound CB-5083. Mol. Pharmacol., 2019, 95(3), 286-293.
[] [PMID: 30591537]
Kang, M.J.; Wu, T.; Wijeratne, E.M.; Lau, E.C.; Mason, D.J.; Mesa, C.; Tillotson, J.; Zhang, D.D.; Gunatilaka, A.A.; La Clair, J.J.; Chapman, E. Functional chromatography reveals three natural products that target the same protein with distinct mechanisms of action. ChemBioChem, 2014, 15(14), 2125-2131.
[] [PMID: 25125376]
Pan, M.; Gao, S.; Zheng, Y.; Tan, X.; Lan, H.; Tan, X.; Sun, D.; Lu, L.; Wang, T.; Zheng, Q.; Huang, Y.; Wang, J.; Liu, L. Quasi-racemic X-ray structures of K27-linked ubiquitin chains prepared by total chemical synthesis. J. Am. Chem. Soc., 2016, 138(23), 7429-7435.
[] [PMID: 27268299]
Tang, S.; Liang, L.J.; Si, Y.Y.; Gao, S.; Wang, J.X.; Liang, J.; Mei, Z.; Zheng, J.S.; Liu, L. Practical chemical synthesis of atypical ubiquitin chains by using an isopeptide-linked Ub isomer. Angew. Chem. Int. Ed. Engl., 2017, 56(43), 13333-13337.
[] [PMID: 28873270]
Chu, G.C.; Pan, M.; Li, J.; Liu, S.; Zuo, C.; Tong, Z.B.; Bai, J.S.; Gong, Q.; Ai, H.; Fan, J.; Meng, X.; Huang, Y.C.; Shi, J.; Deng, H.; Tian, C.; Li, Y.M.; Liu, L. Cysteine-aminoethylation-assisted chemical ubiquitination of recombinant histones. J. Am. Chem. Soc., 2019, 141(8), 3654-3663.
[] [PMID: 30758956]
Morgan, M.; Jbara, M.; Brik, A.; Wolberger, C. Semisynthesis of ubiquitinated histone H2B with a native or nonhydrolyzable linkage. Methods Enzymol., 2019, 618, 1-27.
[] [PMID: 30850047]
Meledin, R.; Mali, S.M.; Kleifeld, O.; Brik, A. Activity-based probes developed by applying a sequential dehydroalanine formation strategy to expressed proteins reveal a potential α-globin-modulating deubiquitinase. Angew. Chem. Int. Ed. Engl., 2018, 57(20), 5645-5649.
[] [PMID: 29527788]
Sun, H.; Mali, S.M.; Singh, S.K.; Meledin, R.; Brik, A.; Kwon, Y.T.; Kravtsova-Ivantsiv, Y.; Bercovich, B.; Ciechanover, A. Diverse fate of ubiquitin chain moieties: The proximal is degraded with the target, and the distal protects the proximal from removal and recycles. Proc. Natl. Acad. Sci. USA, 2019, 116(16), 7805-7812.
[] [PMID: 30867293]
Sun, H.; Meledin, R.; Mali, S.M.; Brik, A. Total chemical synthesis of ester-linked ubiquitinated proteins unravels their behavior with deubiquitinases. Chem. Sci. (Camb.), 2018, 9(6), 1661-1665.
[] [PMID: 29675213]

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