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Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50

The phospholipid cardiolipin mediates the functional interactions of proteins that reside within energy-conserving biological membranes. However, the molecular basis by which this lipid performs this essential cellular role is not well understood. We address this role of cardiolipin using the multis...

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Autores principales: Malhotra, Ketan, Modak, Arnab, Nangia, Shivangi, Daman, Tyler H., Gunsel, Umut, Robinson, Victoria L., Mokranjac, Dejana, May, Eric R., Alder, Nathan N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580885/
https://www.ncbi.nlm.nih.gov/pubmed/28879236
http://dx.doi.org/10.1126/sciadv.1700532
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author Malhotra, Ketan
Modak, Arnab
Nangia, Shivangi
Daman, Tyler H.
Gunsel, Umut
Robinson, Victoria L.
Mokranjac, Dejana
May, Eric R.
Alder, Nathan N.
author_facet Malhotra, Ketan
Modak, Arnab
Nangia, Shivangi
Daman, Tyler H.
Gunsel, Umut
Robinson, Victoria L.
Mokranjac, Dejana
May, Eric R.
Alder, Nathan N.
author_sort Malhotra, Ketan
collection PubMed
description The phospholipid cardiolipin mediates the functional interactions of proteins that reside within energy-conserving biological membranes. However, the molecular basis by which this lipid performs this essential cellular role is not well understood. We address this role of cardiolipin using the multisubunit mitochondrial TIM23 protein transport complex as a model system. The early stages of protein import by this complex require specific interactions between the polypeptide substrate receptor, Tim50, and the membrane-bound channel-forming subunit, Tim23. Using analyses performed in vivo, in isolated mitochondria, and in reductionist nanoscale model membrane systems, we show that the soluble receptor domain of Tim50 interacts with membranes and with specific sites on the Tim23 channel in a manner that is directly modulated by cardiolipin. To obtain structural insights into the nature of these interactions, we obtained the first small-angle x-ray scattering-based structure of the soluble Tim50 receptor in its entirety. Using these structural insights, molecular dynamics simulations combined with a range of biophysical measurements confirmed the role of cardiolipin in driving the association of the Tim50 receptor with lipid bilayers with concomitant structural changes, highlighting the role of key structural elements in mediating this interaction. Together, these results show that cardiolipin is required to mediate specific receptor-channel associations in the TIM23 complex. Our results support a new working model for the dynamic structural changes that occur within the complex during transport. More broadly, this work strongly advances our understanding of how cardiolipin mediates interactions among membrane-associated proteins.
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spelling pubmed-55808852017-09-06 Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50 Malhotra, Ketan Modak, Arnab Nangia, Shivangi Daman, Tyler H. Gunsel, Umut Robinson, Victoria L. Mokranjac, Dejana May, Eric R. Alder, Nathan N. Sci Adv Research Articles The phospholipid cardiolipin mediates the functional interactions of proteins that reside within energy-conserving biological membranes. However, the molecular basis by which this lipid performs this essential cellular role is not well understood. We address this role of cardiolipin using the multisubunit mitochondrial TIM23 protein transport complex as a model system. The early stages of protein import by this complex require specific interactions between the polypeptide substrate receptor, Tim50, and the membrane-bound channel-forming subunit, Tim23. Using analyses performed in vivo, in isolated mitochondria, and in reductionist nanoscale model membrane systems, we show that the soluble receptor domain of Tim50 interacts with membranes and with specific sites on the Tim23 channel in a manner that is directly modulated by cardiolipin. To obtain structural insights into the nature of these interactions, we obtained the first small-angle x-ray scattering-based structure of the soluble Tim50 receptor in its entirety. Using these structural insights, molecular dynamics simulations combined with a range of biophysical measurements confirmed the role of cardiolipin in driving the association of the Tim50 receptor with lipid bilayers with concomitant structural changes, highlighting the role of key structural elements in mediating this interaction. Together, these results show that cardiolipin is required to mediate specific receptor-channel associations in the TIM23 complex. Our results support a new working model for the dynamic structural changes that occur within the complex during transport. More broadly, this work strongly advances our understanding of how cardiolipin mediates interactions among membrane-associated proteins. American Association for the Advancement of Science 2017-09-01 /pmc/articles/PMC5580885/ /pubmed/28879236 http://dx.doi.org/10.1126/sciadv.1700532 Text en Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Malhotra, Ketan
Modak, Arnab
Nangia, Shivangi
Daman, Tyler H.
Gunsel, Umut
Robinson, Victoria L.
Mokranjac, Dejana
May, Eric R.
Alder, Nathan N.
Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50
title Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50
title_full Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50
title_fullStr Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50
title_full_unstemmed Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50
title_short Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50
title_sort cardiolipin mediates membrane and channel interactions of the mitochondrial tim23 protein import complex receptor tim50
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580885/
https://www.ncbi.nlm.nih.gov/pubmed/28879236
http://dx.doi.org/10.1126/sciadv.1700532
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