Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 7, Pages 1732-1737Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1617220114
Keywords
mitochondria; mass spectrometry; interactome; cross-linking; protein interaction reporter
Categories
Funding
- American Heart Association-American Stroke Association [13POST16200007] Funding Source: Medline
- NCATS NIH HHS [UL1 TR001863] Funding Source: Medline
- NCRR NIH HHS [S10 RR025107] Funding Source: Medline
- NHLBI NIH HHS [R01 HL110879, R01 HL110349, R01 HL129510] Funding Source: Medline
- NIAID NIH HHS [U19 AI107775, R01 AI101307] Funding Source: Medline
- NIA NIH HHS [R01 AG047632] Funding Source: Medline
- NIGMS NIH HHS [R01 GM086688] Funding Source: Medline
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Mitochondrial protein interactions and complexes facilitate mitochondrial function. These complexes range from simple dimers to the respirasome supercomplex consisting of oxidative phosphorylation complexes I, III, and IV. To improve understanding of mitochondrial function, we used chemical cross-linking mass spectrometry to identify 2,427 cross-linked peptide pairs from 327 mitochondrial proteins in whole, respiring murine mitochondria. In situ interactions were observed in proteins throughout the electron transport chain membrane complexes, ATP synthase, and the mitochondrial contact site and cristae organizing system (MICOS) complex. Cross-linked sites showed excellent agreement with empirical protein structures and delivered complementary constraints for in silico protein docking. These data established direct physical evidence of the assembly of the complex I-III respirasome and enabled prediction of in situ interfacial regions of the complexes. Finally, we established a database and tools to harness the cross-linked interactions we observed as molecular probes, allowing quantification of conformation-dependent protein interfaces and dynamic protein complex assembly.
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