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6f0x

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Cryo-EM structure of TRIP13 in complex with ATP gamma S, p31comet, C-Mad2 and Cdc20

6f0x, resolution 4.60Å

Structural highlights

6f0x is a 9 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	TRIP13, PCH2 (HUMAN), CDC20 (HUMAN), MAD2L1, MAD2 (HUMAN)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MD2L1_HUMAN] Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. Required for the execution of the mitotic checkpoint which monitors the process of kinetochore-spindle attachment and inhibits the activity of the anaphase promoting complex by sequestering CDC20 until all chromosomes are aligned at the metaphase plate.^[1] ^[2] ^[3] [PCH2_HUMAN] Plays a key role in chromosome recombination and chromosome structure development during meiosis. Required at early steps in meiotic recombination that leads to non-crossovers pathways. Also needed for efficient completion of homologous synapsis by influencing crossover distribution along the chromosomes affecting both crossovers and non-crossovers pathways. Also required for development of higher-order chromosome structures and is needed for synaptonemal-complex formation. In males, required for efficient synapsis of the sex chromosomes and for sex body formation. Promotes early steps of the DNA double-strand breaks (DSBs) repair process upstream of the assembly of RAD51 complexes. Required for depletion of HORMAD1 and HORMAD2 from synapsed chromosomes (By similarity). [CDC20_HUMAN] Required for full ubiquitin ligase activity of the anaphase promoting complex/cyclosome (APC/C) and may confer substrate specificity upon the complex. Is regulated by MAD2L1: in metaphase the MAD2L1-CDC20-APC/C ternary complex is inactive and in anaphase the CDC20-APC/C binary complex is active in degrading substrates. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 induces presynaptic differentiation.^[4] ^[5] ^[6] [MD2BP_HUMAN] May function to silence the spindle checkpoint and allow mitosis to proceed through anaphase by binding MAD2L1 after it has become dissociated from the MAD2L1-CDC20 complex.^[7] ^[8]

Publication Abstract from PubMed

The maintenance of genome stability during mitosis is coordinated by the spindle assembly checkpoint (SAC) through its effector the mitotic checkpoint complex (MCC), an inhibitor of the anaphase-promoting complex (APC/C, also known as the cyclosome)(1,2). Unattached kinetochores control MCC assembly by catalysing a change in the topology of the beta-sheet of MAD2 (an MCC subunit), thereby generating the active closed MAD2 (C-MAD2) conformer(3-5). Disassembly of free MCC, which is required for SAC inactivation and chromosome segregation, is an ATP-dependent process driven by the AAA+ ATPase TRIP13. In combination with p31(comet), an SAC antagonist(6), TRIP13 remodels C-MAD2 into inactive open MAD2 (O-MAD2)(7-10). Here, we present a mechanism that explains how TRIP13-p31(comet) disassembles the MCC. Cryo-electron microscopy structures of the TRIP13-p31(comet)-C-MAD2-CDC20 complex reveal that p31(comet) recruits C-MAD2 to a defined site on the TRIP13 hexameric ring, positioning the N terminus of C-MAD2 (MAD2(NT)) to insert into the axial pore of TRIP13 and distorting the TRIP13 ring to initiate remodelling. Molecular modelling suggests that by gripping MAD2(NT) within its axial pore, TRIP13 couples sequential ATP-driven translocation of its hexameric ring along MAD2(NT) to push upwards on, and simultaneously rotate, the globular domains of the p31(comet)-C-MAD2 complex. This unwinds a region of the alphaA helix of C-MAD2 that is required to stabilize the C-MAD2 beta-sheet, thus destabilizing C-MAD2 in favour of O-MAD2 and dissociating MAD2 from p31(comet). Our study provides insights into how specific substrates are recruited to AAA+ ATPases through adaptor proteins and suggests a model of how translocation through the axial pore of AAA+ ATPases is coupled to protein remodelling.

Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13.,Alfieri C, Chang L, Barford D Nature. 2018 Jul;559(7713):274-278. doi: 10.1038/s41586-018-0281-1. Epub 2018 Jul, 4. PMID:29973720^[9]

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

References

↑ Luo X, Fang G, Coldiron M, Lin Y, Yu H, Kirschner MW, Wagner G. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nat Struct Biol. 2000 Mar;7(3):224-9. PMID:10700282 doi:10.1038/73338
↑ Luo X, Tang Z, Rizo J, Yu H. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Mol Cell. 2002 Jan;9(1):59-71. PMID:11804586
↑ Luo X, Tang Z, Xia G, Wassmann K, Matsumoto T, Rizo J, Yu H. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat Struct Mol Biol. 2004 Apr;11(4):338-45. Epub 2004 Mar 14. PMID:15024386 doi:10.1038/nsmb748
↑ Kramer ER, Gieffers C, Holzl G, Hengstschlager M, Peters JM. Activation of the human anaphase-promoting complex by proteins of the CDC20/Fizzy family. Curr Biol. 1998 Nov 5;8(22):1207-10. PMID:9811605
↑ Fang G, Yu H, Kirschner MW. Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1. Mol Cell. 1998 Aug;2(2):163-71. PMID:9734353
↑ Fang G, Yu H, Kirschner MW. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev. 1998 Jun 15;12(12):1871-83. PMID:9637688
↑ Habu T, Kim SH, Weinstein J, Matsumoto T. Identification of a MAD2-binding protein, CMT2, and its role in mitosis. EMBO J. 2002 Dec 2;21(23):6419-28. PMID:12456649
↑ Yang M, Li B, Tomchick DR, Machius M, Rizo J, Yu H, Luo X. p31comet blocks Mad2 activation through structural mimicry. Cell. 2007 Nov 16;131(4):744-55. PMID:18022368 doi:10.1016/j.cell.2007.08.048
↑ Alfieri C, Chang L, Barford D. Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13. Nature. 2018 Jul;559(7713):274-278. doi: 10.1038/s41586-018-0281-1. Epub 2018 Jul, 4. PMID:29973720 doi:http://dx.doi.org/10.1038/s41586-018-0281-1

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6f0x"

@@ Line 1: / Line 1: @@
 ==Cryo-EM structure of TRIP13 in complex with ATP gamma S, p31comet, C-Mad2 and Cdc20==
-<StructureSection load='6f0x' size='340' side='right' caption='[[6f0x]], [[Resolution|resolution]] 4.60&Aring;' scene=''>
+<SX load='6f0x' size='340' side='right' viewer='molstar' caption='[[6f0x]], [[Resolution|resolution]] 4.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6f0x]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F0X FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6f0x]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F0X OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6F0X FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRIP13, PCH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CDC20 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), MAD2L1, MAD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6f0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f0x OCA], [http://pdbe.org/6f0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f0x RCSB], [http://www.ebi.ac.uk/pdbsum/6f0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f0x ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6f0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f0x OCA], [http://pdbe.org/6f0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f0x RCSB], [http://www.ebi.ac.uk/pdbsum/6f0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f0x ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 <references/>
 __TOC__
-</StructureSection>
+</SX>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Alfieri, C]]
 [[Category: Barford, D]]

6f0x

From Proteopedia

Current revision

Cryo-EM structure of TRIP13 in complex with ATP gamma S, p31comet, C-Mad2 and Cdc20

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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