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Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling

View ORCID ProfileJimin Pei, Jing Zhang, View ORCID ProfileQian Cong
doi: https://doi.org/10.1101/2021.09.14.460228
Jimin Pei
McDermott Center for Human Growth and Development, University of Texas Southwestern, Medical Center at Dallas, 6001 Forest Park Rd., Dallas, TX, USA, Texas, U.S.A. 75390
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Jing Zhang
McDermott Center for Human Growth and Development, University of Texas Southwestern, Medical Center at Dallas, 6001 Forest Park Rd., Dallas, TX, USA, Texas, U.S.A. 75390
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Qian Cong
McDermott Center for Human Growth and Development, University of Texas Southwestern, Medical Center at Dallas, 6001 Forest Park Rd., Dallas, TX, USA, Texas, U.S.A. 75390
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  • For correspondence: qian.cong@utsouthwestern.edu
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Abstract

Recent development of deep-learning methods has led to a breakthrough in the prediction accuracy of 3-dimensional protein structures. Extending these methods to protein pairs is expected to allow large-scale detection of protein-protein interactions and modeling protein complexes at the proteome level. We applied RoseTTAFold and AlphaFold2, two of the latest deep-learning methods for structure predictions, to analyze coevolution of human proteins residing in mitochondria, an organelle of vital importance in many cellular processes including energy production, metabolism, cell death, and antiviral response. Variations in mitochondrial proteins have been linked to a plethora of human diseases and genetic conditions. RoseTTAFold, with high computational speed, was used to predict the coevolution of about 95% of mitochondrial protein pairs. Top-ranked pairs were further subject to the modeling of the complex structures by AlphaFold2, which also produced contact probability with high precision and in many cases consistent with RoseTTAFold. Most of the top ranked pairs with high contact probability were supported by known protein-protein interactions and/or similarities to experimental structural complexes. For high-scoring pairs without experimental complex structures, our coevolution analyses and structural models shed light on the details of their interfaces, including CHCHD4-AIFM1, MTERF3-TRUB2, FMC1-ATPAF2, ECSIT-NDUFAF1 and COQ7-COQ9, among others. We also identified novel PPIs (PYURF-NDUFAF5, LYRM1-MTRF1L and COA8-COX10) for several proteins without experimentally characterized interaction partners, leading to predictions of their molecular functions and the biological processes they are involved in.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 14, 2021.
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Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling
Jimin Pei, Jing Zhang, Qian Cong
bioRxiv 2021.09.14.460228; doi: https://doi.org/10.1101/2021.09.14.460228
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Human mitochondrial protein complexes revealed by large-scale coevolution analysis and deep learning-based structure modeling
Jimin Pei, Jing Zhang, Qian Cong
bioRxiv 2021.09.14.460228; doi: https://doi.org/10.1101/2021.09.14.460228

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