Small-molecule modulators of the ATPase VCP/p97 affect specific p97 cellular functions

Article Article scientifique Article Small-molecule modulators of the ATPase VCP/p97 affect specific p97 cellular functions eng 2020 author Figuerola Conchas Ainoa 805529 author Saarbach Jacques 827625 author Daguer Jean Pierre 809701 author Cieren Adeline 853465 author Barluenga Badiola Sofia 810177 author Winssinger Nicolas 769664 author Gotta Monica 0000-0002-4336-7860 659510 243-253 10.1021/acschembio.9b00832 31790201 1554-8929 https://pubs.acs.org/doi/10.1021/acschembio.9b00832 VCP/p97 belongs to the AAA+ ATPase family and has an essential role in several cellular processes ranging from cell division to protein homeostasis. Compounds targeting p97 inhibit the main ATPase domain and cause cell death. Here, using PNA-encoded chemical libraries, we have identified two small molecules that target the regulatory domain of p97, comprising the N-terminal and the D1 ATPase domains, and do not cause cell death. One molecule, NW1028, inhibits the degradation of a p97-dependent reporter, whereas the other, NW1030, increases it. ATPase assays show that NW1028 and NW1030 do not affect the main catalytic domain of p97. Mapping of the binding site using a photoaffinity conjugate points to a cleft at the interface of the N-terminal and the D1 ATPase domains. We have therefore discovered two new compounds that bind to the regulatory domain of p97 and modulate specific p97 cellular functions. Using these compounds, we have revealed a role for p97 in the regulation of mitotic spindle orientation in HeLa cells. Dewey 540 Dewey 612 Swiss National Science Foundation 185898 CH 36 Département de chimie organique 141 134 Département de physiologie cellulaire et métabolisme 21C false 762 Groupe Winssinger 509 La division asymétrique 847 ACS Chemical Biology 15 1 47baef75-adb9-4507-89ab-c863e3895359 Article (Published version) Restricted acschembio.9b00832.pdf 4949659 application/pdf 34907eb8-ac1d-4254-be3a-63cc668dea02 Supplemental data Restricted cb9b00832_si_001.pdf 4464015 application/pdf 9a910e75-59ae-4935-8f95-9b9b73ad7fe0 Supplemental data Restricted cb9b00832_si_002.avi 2003708 application/x-troff-msvideo f428a6322a9ab594678fcee619420c8d01d0a9ef9bdc7ba19cf80e4e0ffa10af f2705855-fd9d-4ac1-8feb-b95ea024c434 Supplemental data Restricted cb9b00832_si_003.avi 92176 application/x-troff-msvideo d33048e89bb1e74640209b1c7cdcdca2bb3d3b661364b1a094df1d932d9f0fcb 34eed2c9-d761-42f2-8849-a44d95787f27 Supplemental data Restricted cb9b00832_si_004.avi 115178 application/x-troff-msvideo bfa45898f6ef0440f43406043729b2384deb19190ee5eaf5376299768a0d4395 b940f572-7c58-4a84-9675-feffc47ff9ed Supplemental data Restricted cb9b00832_si_005.avi 93084 application/x-troff-msvideo 13917f6d0cb6e00ff4c2fe637a4d1be06fa19a12d06d0028705546115c9829b6 eea33fd7-12ec-4de8-ab9d-da4ee028c682 Article (Accepted version) Public 153-Small molecules p97-Figuerola-ACS CB2020.pdf 4946870 application/pdf Vignette Public cb9b00832_0008.jpeg 85497 image/jpeg openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

Title	Published in	Year	Views	Downloads

Small-molecule modulators of the ATPase VCP/p97 affect specific p97 cellular functions	ACS Chemical Biology	2020	517	482
The AAA ATPase p97: from the use of genetics to the development of new chemical tools to study its functions		2018	976	0

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Figuerola Conchas, Ainoa