Alternative titles; symbols
HGNC Approved Gene Symbol: TOMM40
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:44,891,254-44,903,689 (from NCBI)
TOMM40 is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM) complex that is essential for protein import into mitochondria (Humphries et al., 2005).
By sequencing a cosmid clone, Freitas et al. (1998) identified TOMM40, which they designated PEREC1. The deduced protein contains 362 amino acids. PCR analysis detected expression of TOMM40 in colon and kidney.
Suzuki et al. (2000) cloned rat Tomm40. The deduced protein contains 361 amino acids. Western blot analysis detected rat Tomm40 at an apparent molecular mass of 38 kD. Fractionation of rat liver detected Tomm40 within the mitochondrial fraction. Extraction and antibody-accessibility studies suggested that Tomm40 is embedded within the mitochondrial membrane.
By immunoprecipitation, Suzuki et al. (2000) found that rat Tomm40 was associated with a 400-kD complex containing the mitochondrial import receptors Tom20 (601848) and Tom22 (607046) and several smaller components. Mitochondria-targeted preproteins interacted with the Tomm40-containing complex during their transit to the mitochondrial matrix, and immunodepletion of Tomm40 caused the loss of preprotein import activity.
The precursors of many proteins destined for internal mitochondrial compartments interact first with the TOM complex, then with TIM23 (TIMM23; 605034)- or TIM54-containing translocase complexes of the inner mitochondrial membrane. Using a library of Tom40 yeast mutants, Gabriel et al. (2003) identified a trp243-to-arg (W243R) mutation that specifically interfered with the transfer of proteins from TOM to the TIM23 complex. The trp residue altered by the mutation is conserved between humans and yeast.
Humphries et al. (2005) found that HSP90 (see HSPCA; 140571) was involved in delivery of the TOM40 precursor to mitochondria in an ATP-dependent manner. The precursor then formed its first stable intermediate with the outer face of the TOM complex before its membrane integration and assembly. Deletion of an evolutionarily conserved region within TOM40 disrupted the TOM complex intermediate and caused it to stall in association with the sorting and assembly machinery (SAM) complex of the outer membrane. Depletion of SAM50 (612058), a SAM complex component, reduced TOM40 assembly in mitochondria.
Freitas et al. (1998) determined that the TOMM40 gene contains 9 exons and spans about 12 kb.
Crystal Structure
Shiota et al. (2015) used a crosslinking approach to map the active TOM complex down to single amino acid residues, revealing different transport paths for preproteins through the Tom40 channel. An N-terminal segment of Tom40 passes from the cytosol through the channel to recruit chaperones from the intermembrane space that guide the transfer of hydrophobic preproteins. The translocator contains 3 Tom40 beta-barrel channels sandwiched between a central alpha-helical Tom22 receptor cluster and external regulatory Tom proteins. The preprotein-translocating trimeric complex exchanges with a dimeric isoform to assemble new TOM complexes. Dynamic coupling of alpha-helical receptors, beta-barrel channels, and chaperones generates a versatile machinery that transports about 1,000 different proteins.
By genomic sequence analysis, Freitas et al. (1998) mapped the TOMM40 gene to chromosome 19q13.2, where it lies telomeric to the PRR2 gene (600798) and centromeric to the APOE (107741)-APOC2 (608083) gene cluster.
Freitas, E. M., Zhang, W. J., Lalonde, J.-P., Tay, G. K., Gaudieri, S., Ashworth, L. K., van Bockxmeer, F. M., Dawkins, R. L. Sequencing of 42kb of the APO E-C2 gene cluster reveals a new gene: PEREC1. DNA Seq. 9: 89-101, 1998. [PubMed: 10520737] [Full Text: https://doi.org/10.3109/10425179809086433]
Gabriel, K., Egan, B., Lithgow, T. Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins. EMBO J. 22: 2380-2386, 2003. [PubMed: 12743032] [Full Text: https://doi.org/10.1093/emboj/cdg229]
Humphries, A. D., Streimann, I. C., Stojanovski, D., Johnston, A. J., Yano, M., Hoogenraad, N. J., Ryan, M. T. Dissection of the mitochondrial import and assembly pathway for human Tom40. J. Biol. Chem. 280: 11535-11543, 2005. [PubMed: 15644312] [Full Text: https://doi.org/10.1074/jbc.M413816200]
Shiota, T., Imai, K., Qiu, J., Hewitt, V. L., Tan, K., Shen, H.-H., Sakiyama, N., Fukasawa, Y., Hayat, S., Kamiya, M., Elofsson, A., Tomii, K., Horton, P., Wiedemann, N., Pfanner, N., Lithgow, T., Endo, T. Molecular architecture of the active mitochondrial protein gate. Science 349: 1544-1548, 2015. [PubMed: 26404837] [Full Text: https://doi.org/10.1126/science.aac6428]
Suzuki, H., Okazawa, Y., Komiya, T., Saeki, K., Mekada, E., Kitada, S., Ito, A., Mihara, K. Characterization of rat TOM40, a central component of the preprotein translocase of the mitochondrial outer membrane. J. Biol. Chem. 275: 37930-37936, 2000. [PubMed: 10980201] [Full Text: https://doi.org/10.1074/jbc.M006558200]