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 207d2e8d-f272-48ef-8c29-012b6c40221e Supplemental data Restricted Documents2.xspf 587 application/xml e4beae6f-23cc-4f3c-b720-802f9afa7aa9 Supplemental data Restricted Documents3.xspf 584 application/xml 74181e55-5bec-4b6e-a973-a3c853c5642a Supplemental data Restricted Documents4.xspf 584 application/xml 26f9b379-d243-4559-9a8a-a35aa44ae97e Supplemental data Restricted Documents5.xspf 584 application/xml 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	427	333
The AAA ATPase p97: from the use of genetics to the development of new chemical tools to study its functions		2018	826	0

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Figuerola Conchas, Ainoa