8fcm: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 1: Line 1:
'''Unreleased structure'''


The entry 8fcm is ON HOLD  until Paper Publication
==Cryo-EM structure of p97:UBXD1 open state==
<StructureSection load='8fcm' size='340' side='right'caption='[[8fcm]], [[Resolution|resolution]] 3.27&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8fcm]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FCM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FCM FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8fcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fcm OCA], [https://pdbe.org/8fcm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fcm RCSB], [https://www.ebi.ac.uk/pdbsum/8fcm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fcm ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/UBXN6_HUMAN UBXN6_HUMAN] May negatively regulate the ATPase activity of VCP, an ATP-driven segregase that associates with different cofactors to control a wide variety of cellular processes (PubMed:26475856). As a cofactor of VCP, it may play a role in the transport of CAV1 to lysosomes for degradation (PubMed:21822278, PubMed:23335559). It may also play a role in endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins (PubMed:19275885). Together with VCP and other cofactors, it may play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes (PubMed:27753622).<ref>PMID:19275885</ref> <ref>PMID:21822278</ref> <ref>PMID:23335559</ref> <ref>PMID:26475856</ref> <ref>PMID:27753622</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
p97/VCP is an essential cytosolic AAA+ ATPase hexamer that extracts and unfolds substrate polypeptides during protein homeostasis and degradation. Distinct sets of p97 adapters guide cellular functions but their roles in direct control of the hexamer are unclear. The UBXD1 adapter localizes with p97 in critical mitochondria and lysosome clearance pathways and contains multiple p97-interacting domains. We identify UBXD1 as a potent p97 ATPase inhibitor and report structures of intact p97:UBXD1 complexes that reveal extensive UBXD1 contacts across p97 and an asymmetric remodeling of the hexamer. Conserved VIM, UBX, and PUB domains tether adjacent protomers while a connecting strand forms an N-terminal domain lariat with a helix wedged at the interprotomer interface. An additional VIM-connecting helix binds along the second AAA+ domain. Together these contacts split the hexamer into a ring-open conformation. Structures, mutagenesis, and comparisons to other adapters further reveal how adapters containing conserved p97-remodeling motifs regulate p97 ATPase activity and structure.


Authors:  
The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.,Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, Southworth DR bioRxiv. 2023 May 15:2023.05.15.540864. doi: 10.1101/2023.05.15.540864. Preprint. PMID:37292947<ref>PMID:37292947</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 8fcm" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Braxton JR]]
[[Category: Southworth DR]]
[[Category: Tse E]]
[[Category: Tucker MR]]

Revision as of 12:38, 21 June 2023

Cryo-EM structure of p97:UBXD1 open stateCryo-EM structure of p97:UBXD1 open state

Structural highlights

8fcm is a 7 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UBXN6_HUMAN May negatively regulate the ATPase activity of VCP, an ATP-driven segregase that associates with different cofactors to control a wide variety of cellular processes (PubMed:26475856). As a cofactor of VCP, it may play a role in the transport of CAV1 to lysosomes for degradation (PubMed:21822278, PubMed:23335559). It may also play a role in endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins (PubMed:19275885). Together with VCP and other cofactors, it may play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes (PubMed:27753622).[1] [2] [3] [4] [5]

Publication Abstract from PubMed

p97/VCP is an essential cytosolic AAA+ ATPase hexamer that extracts and unfolds substrate polypeptides during protein homeostasis and degradation. Distinct sets of p97 adapters guide cellular functions but their roles in direct control of the hexamer are unclear. The UBXD1 adapter localizes with p97 in critical mitochondria and lysosome clearance pathways and contains multiple p97-interacting domains. We identify UBXD1 as a potent p97 ATPase inhibitor and report structures of intact p97:UBXD1 complexes that reveal extensive UBXD1 contacts across p97 and an asymmetric remodeling of the hexamer. Conserved VIM, UBX, and PUB domains tether adjacent protomers while a connecting strand forms an N-terminal domain lariat with a helix wedged at the interprotomer interface. An additional VIM-connecting helix binds along the second AAA+ domain. Together these contacts split the hexamer into a ring-open conformation. Structures, mutagenesis, and comparisons to other adapters further reveal how adapters containing conserved p97-remodeling motifs regulate p97 ATPase activity and structure.

The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.,Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, Southworth DR bioRxiv. 2023 May 15:2023.05.15.540864. doi: 10.1101/2023.05.15.540864. Preprint. PMID:37292947[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Nagahama M, Ohnishi M, Kawate Y, Matsui T, Miyake H, Yuasa K, Tani K, Tagaya M, Tsuji A. UBXD1 is a VCP-interacting protein that is involved in ER-associated degradation. Biochem Biophys Res Commun. 2009 May 1;382(2):303-8. doi:, 10.1016/j.bbrc.2009.03.012. Epub 2009 Mar 9. PMID:19275885 doi:http://dx.doi.org/10.1016/j.bbrc.2009.03.012
  2. ↑ Ritz D, Vuk M, Kirchner P, Bug M, Schutz S, Hayer A, Bremer S, Lusk C, Baloh RH, Lee H, Glatter T, Gstaiger M, Aebersold R, Weihl CC, Meyer H. Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations. Nat Cell Biol. 2011 Aug 7;13(9):1116-23. doi: 10.1038/ncb2301. PMID:21822278 doi:http://dx.doi.org/10.1038/ncb2301
  3. ↑ Kirchner P, Bug M, Meyer H. Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal sorting by the VCP/p97 AAA-ATPase. J Biol Chem. 2013 Mar 8;288(10):7363-72. doi: 10.1074/jbc.M112.429076. Epub 2013 , Jan 19. PMID:23335559 doi:http://dx.doi.org/10.1074/jbc.M112.429076
  4. ↑ Trusch F, Matena A, Vuk M, Koerver L, Knaevelsrud H, Freemont PS, Meyer H, Bayer P. The N-terminal Region of the Ubiquitin Regulatory X (UBX) Domain-containing Protein 1 (UBXD1) Modulates Interdomain Communication within the Valosin-containing Protein p97. J Biol Chem. 2015 Dec 4;290(49):29414-27. doi: 10.1074/jbc.M115.680686. Epub 2015, Oct 16. PMID:26475856 doi:http://dx.doi.org/10.1074/jbc.M115.680686
  5. ↑ 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 CC, Meyer H. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J. 2017 Jan 17;36(2):135-150. doi: 10.15252/embj.201695148. Epub 2016 Oct, 17. PMID:27753622 doi:http://dx.doi.org/10.15252/embj.201695148
  6. ↑ Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, Southworth DR. The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions. bioRxiv. 2023 May 15:2023.05.15.540864. PMID:37292947 doi:10.1101/2023.05.15.540864

8fcm, resolution 3.27Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=8fcm&oldid=3792603"