View source for 6pek


==Structure of Spastin Hexamer (Subunit A-E) in complex with substrate peptide==
<SX load='6pek' size='340' side='right' viewer='molstar' caption='[[6pek]], [[Resolution|resolution]] 4.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6pek]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PEK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PEK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.2&#8491;</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>, <scene name='pdbligand=BEF:BERYLLIUM+TRIFLUORIDE+ION'>BEF</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=6pek FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pek OCA], [https://pdbe.org/6pek PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pek RCSB], [https://www.ebi.ac.uk/pdbsum/6pek PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pek ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SPAST_HUMAN SPAST_HUMAN] Defects in SPAST are the cause of spastic paraplegia autosomal dominant type 4 (SPG4) [MIM:[https://omim.org/entry/182601 182601]. Spastic paraplegia is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG4 is the most common form of autosomal dominant spastic paraplegias.<ref>PMID:11809724</ref> <ref>PMID:15716377</ref> <ref>PMID:17389232</ref> <ref>PMID:19000169</ref> <ref>PMID:16339213</ref> <ref>PMID:15891913</ref> <ref>PMID:10610178</ref> <ref>PMID:11039577</ref> <ref>PMID:10699187</ref> <ref>PMID:11015453</ref> <ref>PMID:11087788</ref> <ref>PMID:11309678</ref> <ref>PMID:12460147</ref> <ref>PMID:11843700</ref> <ref>PMID:12124993</ref> <ref>PMID:12161613</ref> <ref>PMID:11985387</ref> <ref>PMID:12163196</ref> <ref>PMID:12202986</ref> <ref>PMID:12552568</ref> <ref>PMID:12939659</ref> <ref>PMID:14732620</ref> <ref>PMID:15210521</ref> <ref>PMID:15248095</ref> <ref>PMID:15482961</ref> <ref>PMID:15159500</ref> <ref>PMID:15326248</ref> <ref>PMID:16682546</ref> <ref>PMID:16684598</ref> <ref>PMID:17594340</ref> <ref>PMID:20214791</ref> <ref>PMID:20932283</ref> <ref>PMID:20562464</ref> <ref>PMID:20718791</ref> <ref>PMID:20550563</ref> 
== Function ==
[https://www.uniprot.org/uniprot/SPAST_HUMAN SPAST_HUMAN] ATP-dependent microtubule severing protein. Microtubule severing may promote reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and for completion of the abscission stage of cytokinesis. May also play a role in axon growth and the formation of axonal branches.<ref>PMID:11809724</ref> <ref>PMID:12676568</ref> <ref>PMID:15716377</ref> <ref>PMID:16219033</ref> <ref>PMID:17389232</ref> <ref>PMID:19000169</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Many members of the AAA+ ATPase family function as hexamers that unfold their protein substrates. These AAA unfoldases include spastin, which plays a critical role in the architecture of eukaryotic cells by driving the remodeling and severing of microtubules, which are cytoskeletal polymers of tubulin subunits. Here, we demonstrate that a human spastin binds weakly to unmodified peptides from the C-terminal segment of human tubulin a1A/B. A peptide comprising alternating glutamate and tyrosine residues binds more tightly, which is consistent with the known importance of glutamylation for spastin microtubule severing activity. A cryo-EM structure of the spastin-peptide complex at 4.2 A resolution revealed an asymmetric hexamer in which five spastin subunits adopt a helical, spiral staircase configuration that binds the peptide within the central pore, while the sixth subunit of the hexamer is displaced from the peptide/substrate, as if transitioning from one end of the helix to the other. This configuration differs from a recently published structure of spastin from Drosophila melanogaster, which forms a six-subunit spiral without a transitioning subunit. Our structure resembles other recently reported AAA unfoldases, including the meiotic clade relative Vps4, and supports a model in which spastin utilizes a hand-over-hand mechanism of tubulin translocation and microtubule remodeling.

Structure of spastin bound to a glutamate-rich peptide implies a hand-over-hand mechanism of substrate translocation.,Han H, Schubert HL, McCullough J, Monroe N, Purdy MD, Yeager M, Sundquist WI, Hill CP J Biol Chem. 2019 Nov 25. pii: AC119.009890. doi: 10.1074/jbc.AC119.009890. PMID:31767681<ref>PMID:31767681</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6pek" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</SX>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Han H]]
[[Category: Hill CP]]
[[Category: McCullough J]]
[[Category: Monroe N]]
[[Category: Schubert HL]]
[[Category: Sundquist WI]]