6xot: Difference between revisions
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==CryoEM structure of human presequence protease in partial open state 2== | |||
<StructureSection load='6xot' size='340' side='right'caption='[[6xot]], [[Resolution|resolution]] 3.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6xot]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XOT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XOT FirstGlance]. <br> | |||
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PITRM1, KIAA1104, MP1, PREP ([https://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'>[https://proteopedia.org/fgij/fg.htm?mol=6xot FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xot OCA], [https://pdbe.org/6xot PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xot RCSB], [https://www.ebi.ac.uk/pdbsum/6xot PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xot ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/PREP_HUMAN PREP_HUMAN]] ATP-independent protease that degrades mitochondrial transit peptides after their cleavage. Also degrades other unstructured peptides. Specific for peptides in the range of 10 to 65 residues. Able to degrade amyloid beta A4 (APP) protein when it accumulates in mitochondrion, suggesting a link with Alzheimer disease. Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference.<ref>PMID:16849325</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid beta (Abeta). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption. Thereby, we elucidate cryoEM structures of three apo-PreP open states along with Abeta- and citrate synthase presequence-bound PreP at 3.3-4.6 A resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives a rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations. | |||
Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.,Liang WG, Wijaya J, Wei H, Noble AJ, Mancl JM, Mo S, Lee D, Lin King JV, Pan M, Liu C, Koehler CM, Zhao M, Potter CS, Carragher B, Li S, Tang WJ Nat Commun. 2022 Apr 5;13(1):1833. doi: 10.1038/s41467-022-29322-4. PMID:35383169<ref>PMID:35383169</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6xot" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Liang, W G]] | |||
[[Category: Tang, W]] | [[Category: Tang, W]] | ||
[[Category: Zhao, M]] | [[Category: Zhao, M]] | ||
[[Category: | [[Category: Hydrolase]] | ||
[[Category: Partial open state]] | |||
Latest revision as of 13:17, 13 April 2022
CryoEM structure of human presequence protease in partial open state 2CryoEM structure of human presequence protease in partial open state 2
Structural highlights
Function[PREP_HUMAN] ATP-independent protease that degrades mitochondrial transit peptides after their cleavage. Also degrades other unstructured peptides. Specific for peptides in the range of 10 to 65 residues. Able to degrade amyloid beta A4 (APP) protein when it accumulates in mitochondrion, suggesting a link with Alzheimer disease. Shows a preference for cleavage after small polar residues and before basic residues, but without any positional preference.[1] Publication Abstract from PubMedPresequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid beta (Abeta). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption. Thereby, we elucidate cryoEM structures of three apo-PreP open states along with Abeta- and citrate synthase presequence-bound PreP at 3.3-4.6 A resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives a rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations. Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.,Liang WG, Wijaya J, Wei H, Noble AJ, Mancl JM, Mo S, Lee D, Lin King JV, Pan M, Liu C, Koehler CM, Zhao M, Potter CS, Carragher B, Li S, Tang WJ Nat Commun. 2022 Apr 5;13(1):1833. doi: 10.1038/s41467-022-29322-4. PMID:35383169[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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