Structures of PGAM5 provide insight into active site plasticity and multimeric assembly.
PGAM5 is a mitochondrial membrane protein that functions as an atypical Ser/Thr phosphatase and is a regulator of oxidative stress response, necroptosis, and autophagy. Here we present several crystal structures of PGAM5 including the activating N-terminal regulatory sequences, providing a model for...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2017
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| _version_ | 1826306388544978944 |
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| author | Chaikuad, A Filippakopoulos, P Marcsisin, SR Picaud, S Schröder, M Sekine, S Ichijo, H Engen, JR Takeda, K Knapp, S |
| author_facet | Chaikuad, A Filippakopoulos, P Marcsisin, SR Picaud, S Schröder, M Sekine, S Ichijo, H Engen, JR Takeda, K Knapp, S |
| author_sort | Chaikuad, A |
| collection | OXFORD |
| description | PGAM5 is a mitochondrial membrane protein that functions as an atypical Ser/Thr phosphatase and is a regulator of oxidative stress response, necroptosis, and autophagy. Here we present several crystal structures of PGAM5 including the activating N-terminal regulatory sequences, providing a model for structural plasticity, dimerization of the catalytic domain, and the assembly into an enzymatically active dodecameric form. Oligomeric states observed in structures were supported by hydrogen exchange mass spectrometry, size-exclusion chromatography, and analytical ultracentrifugation experiments in solution. We report that the catalytically important N-terminal WDPNWD motif acts as a structural integrator assembling PGAM5 into a dodecamer, allosterically activating the phosphatase by promoting an ordering of the catalytic loop. Additionally the observed active site plasticity enabled visualization of essential conformational rearrangements of catalytic elements. The comprehensive biophysical characterization offers detailed structural models of this key mitochondrial phosphatase that has been associated with the development of diverse diseases. |
| first_indexed | 2024-03-07T06:47:13Z |
| format | Journal article |
| id | oxford-uuid:fb44c9b5-211e-4d95-a026-9215d5de7f13 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:47:13Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:fb44c9b5-211e-4d95-a026-9215d5de7f132022-03-27T13:12:35ZStructures of PGAM5 provide insight into active site plasticity and multimeric assembly.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fb44c9b5-211e-4d95-a026-9215d5de7f13EnglishSymplectic Elements at OxfordElsevier2017Chaikuad, AFilippakopoulos, PMarcsisin, SRPicaud, SSchröder, MSekine, SIchijo, HEngen, JRTakeda, KKnapp, SPGAM5 is a mitochondrial membrane protein that functions as an atypical Ser/Thr phosphatase and is a regulator of oxidative stress response, necroptosis, and autophagy. Here we present several crystal structures of PGAM5 including the activating N-terminal regulatory sequences, providing a model for structural plasticity, dimerization of the catalytic domain, and the assembly into an enzymatically active dodecameric form. Oligomeric states observed in structures were supported by hydrogen exchange mass spectrometry, size-exclusion chromatography, and analytical ultracentrifugation experiments in solution. We report that the catalytically important N-terminal WDPNWD motif acts as a structural integrator assembling PGAM5 into a dodecamer, allosterically activating the phosphatase by promoting an ordering of the catalytic loop. Additionally the observed active site plasticity enabled visualization of essential conformational rearrangements of catalytic elements. The comprehensive biophysical characterization offers detailed structural models of this key mitochondrial phosphatase that has been associated with the development of diverse diseases. |
| spellingShingle | Chaikuad, A Filippakopoulos, P Marcsisin, SR Picaud, S Schröder, M Sekine, S Ichijo, H Engen, JR Takeda, K Knapp, S Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. |
| title | Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. |
| title_full | Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. |
| title_fullStr | Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. |
| title_full_unstemmed | Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. |
| title_short | Structures of PGAM5 provide insight into active site plasticity and multimeric assembly. |
| title_sort | structures of pgam5 provide insight into active site plasticity and multimeric assembly |
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