Publications by authors named "Michael A Conti"

2 Publications

  • Page 1 of 1

Stendomycin selectively inhibits TIM23-dependent mitochondrial protein import.

Nat Chem Biol 2017 Dec 9;13(12):1239-1244. Epub 2017 Oct 9.

Novartis Institutes for BioMedical Research, Basel, Switzerland.

Tim17 and Tim23 are the main subunits of the TIM23 complex, one of the two major essential mitochondrial inner-membrane protein translocon machineries (TIMs). No chemical probes that specifically inhibit TIM23-dependent protein import were known to exist. Here we show that the natural product stendomycin, produced by Streptomyces hygroscopicus, is a potent and specific inhibitor of the TIM23 complex in yeast and mammalian cells. Furthermore, stendomycin-mediated blockage of the TIM23 complex does not alter normal processing of the major regulatory mitophagy kinase PINK1, but TIM23 is required to stabilize PINK1 on the outside of mitochondria to initiate mitophagy upon membrane depolarization.
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http://dx.doi.org/10.1038/nchembio.2493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945950PMC
December 2017

Adaptation of a Genetic Screen Reveals an Inhibitor for Mitochondrial Protein Import Component Tim44.

J Biol Chem 2017 Mar 6;292(13):5429-5442. Epub 2017 Feb 6.

From the Departments of Chemistry and Biochemistry and

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 mistargeting 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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http://dx.doi.org/10.1074/jbc.M116.770131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392686PMC
March 2017