期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 13, 页码 5429-5442出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.770131
关键词
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资金
- National Institutes of Health [GM073981, GM61721]
- California Institute of Regenerative Medicine [RS1-00313, RB1-01397]
- National Science Foundation [MCB-0919586]
- U.S. Public Health Service NRSA [GM07185, GM08496]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1350401] Funding Source: National Science Foundation
Diverse protein import pathways into mitochondria use translocons on the outer membrane (TOM) and inner membrane (TIM). We adapted a genetic screen, based on Ura3 mis-targeting from mitochondria to the cytosol, to identify small molecules that attenuated protein import. Small molecule mitochondrial import blockers of the Carla Koehler laboratory (MB)-10 inhibited import of substrates that require the TIM23 translocon. Mutational analysis coupled with molecular docking and molecular dynamics modeling revealed that MB-10 binds to a specific pocket in the C-terminal domain of Tim44 of the protein-associated motor (PAM) complex. This region was proposed to anchor Tim44 to the membrane, but biochemical studies with MB-10 show that this region is required for binding to the translocating precursor and binding to mtHsp70 in low ATP conditions. This study also supports a direct role for the PAM complex in the import of substrates that are laterally sorted to the inner membrane, as well as the mitochondrial matrix. Thus, MB-10 is the first small molecule modulator to attenuate PAM complex activity, likely through binding to the C-terminal region of Tim44.
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