Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier
Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylati...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Jezik: | English |
| Izdano: |
EMBO Press
2024
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| _version_ | 1826313490577489920 |
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| author | Senoo, N Chinthapalli, DK Baile, MG Golla, VK Saha, B Oluwole, AO Ogunbona, OB Saba, JA Munteanu, T Valdez, Y Whited, K Sheridan, MS Chorev, D Alder, NN May, ER Robinson, CV Claypool, SM |
| author_facet | Senoo, N Chinthapalli, DK Baile, MG Golla, VK Saha, B Oluwole, AO Ogunbona, OB Saba, JA Munteanu, T Valdez, Y Whited, K Sheridan, MS Chorev, D Alder, NN May, ER Robinson, CV Claypool, SM |
| author_sort | Senoo, N |
| collection | OXFORD |
| description | Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS). In the inner mitochondrial membrane, the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) exchanges ADP and ATP, enabling OXPHOS. AAC/ANT contains three tightly bound CLs, and these interactions are evolutionarily conserved. Here, we investigated the role of these buried CLs in AAC/ANT using a combination of biochemical approaches, native mass spectrometry, and molecular dynamics simulations. We introduced negatively charged mutations into each CL-binding site of yeast Aac2 and established experimentally that the mutations disrupted the CL interactions. While all mutations destabilized Aac2 tertiary structure, transport activity was impaired in a binding site-specific manner. Additionally, we determined that a disease-associated missense mutation in one CL-binding site in human ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions. |
| first_indexed | 2024-09-25T04:16:00Z |
| format | Journal article |
| id | oxford-uuid:bf85d157-c614-42b2-b100-9562d12ca910 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:16:00Z |
| publishDate | 2024 |
| publisher | EMBO Press |
| record_format | dspace |
| spelling | oxford-uuid:bf85d157-c614-42b2-b100-9562d12ca9102024-07-15T20:15:02ZFunctional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrierJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:bf85d157-c614-42b2-b100-9562d12ca910EnglishJisc Publications RouterEMBO Press2024Senoo, NChinthapalli, DKBaile, MGGolla, VKSaha, BOluwole, AOOgunbona, OBSaba, JAMunteanu, TValdez, YWhited, KSheridan, MSChorev, DAlder, NNMay, ERRobinson, CVClaypool, SMLipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS). In the inner mitochondrial membrane, the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) exchanges ADP and ATP, enabling OXPHOS. AAC/ANT contains three tightly bound CLs, and these interactions are evolutionarily conserved. Here, we investigated the role of these buried CLs in AAC/ANT using a combination of biochemical approaches, native mass spectrometry, and molecular dynamics simulations. We introduced negatively charged mutations into each CL-binding site of yeast Aac2 and established experimentally that the mutations disrupted the CL interactions. While all mutations destabilized Aac2 tertiary structure, transport activity was impaired in a binding site-specific manner. Additionally, we determined that a disease-associated missense mutation in one CL-binding site in human ANT1 compromised its structure and transport activity, resulting in OXPHOS defects. Our findings highlight the conserved significance of CL in AAC/ANT structure and function, directly tied to specific lipid-protein interactions. |
| spellingShingle | Senoo, N Chinthapalli, DK Baile, MG Golla, VK Saha, B Oluwole, AO Ogunbona, OB Saba, JA Munteanu, T Valdez, Y Whited, K Sheridan, MS Chorev, D Alder, NN May, ER Robinson, CV Claypool, SM Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier |
| title | Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier |
| title_full | Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier |
| title_fullStr | Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier |
| title_full_unstemmed | Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier |
| title_short | Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier |
| title_sort | functional diversity among cardiolipin binding sites on the mitochondrial adp atp carrier |
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