8b5r: Difference between revisions

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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8b5r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b5r OCA], [https://pdbe.org/8b5r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b5r RCSB], [https://www.ebi.ac.uk/pdbsum/8b5r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b5r ProSAT]</span></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=8b5r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b5r OCA], [https://pdbe.org/8b5r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b5r RCSB], [https://www.ebi.ac.uk/pdbsum/8b5r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b5r ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/TERA_HUMAN TERA_HUMAN] Defects in VCP are the cause of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) [MIM:[https://omim.org/entry/167320 167320]; also known as muscular dystrophy, limb-girdle, with Paget disease of bone or pagetoid amyotrophic lateral sclerosis or pagetoid neuroskeletal syndrome or lower motor neuron degeneration with Paget-like bone disease. IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset Paget disease of bone in most cases and premature frontotemporal dementia.<ref>PMID:20512113</ref> <ref>PMID:15034582</ref> <ref>PMID:15732117</ref> <ref>PMID:16247064</ref> <ref>PMID:16321991</ref>  Defects in VCP are the cause of amyotrophic lateral sclerosis type 14 with or without frontotemporal dementia (ALS14) [MIM:[https://omim.org/entry/613954 613954]. ALS14 is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS14 may develop frontotemporal dementia.<ref>PMID:21145000</ref>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/TERA_HUMAN TERA_HUMAN] Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1L, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1L-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A (By similarity). Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.<ref>PMID:15456787</ref> <ref>PMID:16168377</ref> <ref>PMID:22020440</ref> <ref>PMID:22120668</ref> <ref>PMID:22607976</ref> <ref>PMID:23042607</ref> <ref>PMID:23042605</ref>  
[https://www.uniprot.org/uniprot/PP1R7_HUMAN PP1R7_HUMAN] Regulatory subunit of protein phosphatase 1.
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== Publication Abstract from PubMed ==
The AAA+-ATPase p97 (also called VCP or Cdc48) unfolds proteins and disassembles protein complexes in numerous cellular processes, but how substrate complexes are loaded onto p97 and disassembled is unclear. Here, we present cryo-EM structures of p97 in the process of disassembling a protein phosphatase-1 (PP1) complex by extracting an inhibitory subunit from PP1. We show that PP1 and its partners SDS22 and inhibitor-3 (I3) are loaded tightly onto p97, surprisingly via a direct contact of SDS22 with the p97 N-domain. Loading is assisted by the p37 adapter that bridges two adjacent p97 N-domains underneath the substrate complex. A stretch of I3 is threaded into the central channel of the spiral-shaped p97 hexamer, while other elements of I3 are still attached to PP1. Thus, our data show how p97 arranges a protein complex between the p97 N-domain and central channel, suggesting a hold-and-extract mechanism for p97-mediated disassembly.
 
Structural basis of ubiquitin-independent PP1 complex disassembly by p97.,van den Boom J, Marini G, Meyer H, Saibil HR EMBO J. 2023 Jul 17;42(14):e113110. doi: 10.15252/embj.2022113110. Epub 2023 Jun , 2. PMID:37264685<ref>PMID:37264685</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8b5r" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Latest revision as of 09:47, 24 July 2024

p97-p37-SPI substrate complexp97-p37-SPI substrate complex

Structural highlights

8b5r is a 11 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 6.1Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PP1R7_HUMAN Regulatory subunit of protein phosphatase 1.

Publication Abstract from PubMed

The AAA+-ATPase p97 (also called VCP or Cdc48) unfolds proteins and disassembles protein complexes in numerous cellular processes, but how substrate complexes are loaded onto p97 and disassembled is unclear. Here, we present cryo-EM structures of p97 in the process of disassembling a protein phosphatase-1 (PP1) complex by extracting an inhibitory subunit from PP1. We show that PP1 and its partners SDS22 and inhibitor-3 (I3) are loaded tightly onto p97, surprisingly via a direct contact of SDS22 with the p97 N-domain. Loading is assisted by the p37 adapter that bridges two adjacent p97 N-domains underneath the substrate complex. A stretch of I3 is threaded into the central channel of the spiral-shaped p97 hexamer, while other elements of I3 are still attached to PP1. Thus, our data show how p97 arranges a protein complex between the p97 N-domain and central channel, suggesting a hold-and-extract mechanism for p97-mediated disassembly.

Structural basis of ubiquitin-independent PP1 complex disassembly by p97.,van den Boom J, Marini G, Meyer H, Saibil HR EMBO J. 2023 Jul 17;42(14):e113110. doi: 10.15252/embj.2022113110. Epub 2023 Jun , 2. PMID:37264685[1]

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

References

  1. ↑ van den Boom J, Marini G, Meyer H, Saibil HR. Structural basis of ubiquitin-independent PP1 complex disassembly by p97. EMBO J. 2023 Jul 17;42(14):e113110. PMID:37264685 doi:10.15252/embj.2022113110

8b5r, resolution 6.10Å

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