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3.A.8.1.1
Mitochondrial protein translocase (MPT) (Chacinska et al., 2005; Mokranjac et al., 2005; Bihlmaier et al., 2007). The crystal structure of the intermembrane space domain of yeast Tim50 has been solved to 1.83 Å resolution (Qian et al., 2011). A protruding beta-hairpin of Tim50 is crucial for interaction with Tim23, providing a molecular basis for the cooperation of Tim50 and Tim23 in preprotein translocation to the protein-conducting channel of the mitochondrial inner membrane (Qian et al., 2011).  TIM23-mediates insertion of transmembrane α-helices into the mitochondrial inner membrane (Botelho et al., 2011). The TIM23 channel undergoes structural changes in response to the energized state of the membrane, the pmf (Malhotra et al. 2013).  TMS1 in TIM23 is required for homodimerization while it and TMS2 are involved in pre-protein binding in the channel (Pareek et al. 2013).  The Tom40 outer membrane channel may be a 19 β-stranded barrel, possibly homologous to the VDAC porins (TC# 1.B.8) (Lackey et al. 2014).  Tim23 and Tim17 interact with each other as well as Tim44 and Pam17, respectively.  These last two proteins may serve regulatory functions (Ting et al. 2014).  Tom20, 22, 40 and 70 recognize presequences in various mitochondrially targetted proteins (Melin et al. 2015; Melin et al. 2014).  In the 4 TMS TIM17 protein, mutations in TMSs1 and 2 impair the interaction of Tim17 with Tim23, whereas mutations in TM3 compromise binding of the import motor (Demishtein-Zohary et al. 2017); further, residues in the matrix-facing region of Tim17 involved in binding of the import motor were identified. TIM22, forms an intramolecular disulfide bond in yeast and humans.  If not oxidized, they do not properly integrate into the membrane complex, and the lack of Tim17 oxidation disrupts the TIM23 translocase complex (Wrobel et al. 2016). Mgr2 (TC# 1.A.111.1.3) and Pam18 are involved in precursormembrane protein quality control (Schendzielorz et al. 2018). Tom7 and OMA1 play reciprocal roles during mitochondrial import and activation of the PTEN-induced kinase 1, PINK1, in humans (Sekine et al. 2019).  Organellar beta-barrel proteins are unique as most of them do not contain typical targeting information in the form of an N-terminal cleavable targeting signal. Instead, targeting and surface recognition of mitochondrial beta-barrel proteins in yeast, humans and plants depends on the hydrophobicity of the last beta-hairpin of the beta-barrel. Klinger et al. 2019 demonstrated that hydrophobicity is not sufficient for the discrimination of targeting to chloroplasts or mitochondria. Using atVDAC1 (TC# 1.B.8.1.15) and psOEP24 (1.B.28.1.1) they showed that the presence of a hydrophilic amino acid at the C-terminus of the penultimate beta-strand is required for mitochondrial targeting. A mutation of the chloroplast beta-barrel protein psOEP24 which mimics such a profile is efficiently targeted to mitochondria (Klinger et al. 2019). The high-resolution cryo-EM structures of the core TOM complex from Saccharomyces cerevisiae in dimeric and tetrameric forms have  been determined (Tucker and Park 2019). Dimeric TOM consists of two copies each of five proteins arranged in two-fold symmetry: pore-forming beta-barrel protein Tom40 and four auxiliary alpha-helical transmembrane proteins. The pore of each Tom40 has an overall negatively charged inner surface due to multiple functionally important acidic patches. The tetrameric complex is a dimer of dimeric TOM, which may be capable of forming higher-order oligomers. Negatively charged residues in the N-terminus of Tim17 are critical for the preprotein-induced gating of the TIM23 translocase, possibly by recognizing the positive charges in the leader sequence of the substrate proteins (Meier et al. 2005).  

Accession Number:P36046
Protein Name:Mia40 aka Tim40
Length:403
Molecular Weight:44536.00
Species:Saccharomyces cerevisiae (Baker's yeast) [4932]
Number of TMSs:1
Location1 / Topology2 / Orientation3: Mitochondrion inner membrane1 / Single-pass type II membrane protein2 / Intermembrane side3
Substrate proteins

Cross database links:

Genevestigator: P36046
eggNOG: fuNOG11502
DIP: DIP-5432N
RefSeq: NP_012726.2   
Entrez Gene ID: 853639   
KEGG: sce:YKL195W   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005743 C:mitochondrial inner membrane
GO:0005758 C:mitochondrial intermembrane space
GO:0005742 C:mitochondrial outer membrane translocase co...
GO:0045041 P:protein import into mitochondrial intermemb...

References (12)

[1] “Complete DNA sequence of yeast chromosome XI.”  Dujon B.et.al.   8196765
[2] “Mia40, a novel factor for protein import into the intermembrane space of mitochondria is able to bind metal ions.”  Terziyska N.et.al.   15620710
[3] “Sequencing and comparison of yeast species to identify genes and regulatory elements.”  Kellis M.et.al.   12748633
[4] “Global analysis of protein localization in budding yeast.”  Huh W.-K.et.al.   14562095
[5] “Global analysis of protein expression in yeast.”  Ghaemmaghami S.et.al.   14562106
[6] “The proteome of Saccharomyces cerevisiae mitochondria.”  Sickmann A.et.al.   14576278
[7] “Essential role of Mia40 in import and assembly of mitochondrial intermembrane space proteins.”  Chacinska A.et.al.   15359280
[8] “Identification of Tim40 that mediates protein sorting to the mitochondrial intermembrane space.”  Naoe M.et.al.   15364952
[9] “A disulfide relay system in the intermembrane space of mitochondria that mediates protein import.”  Mesecke N.et.al.   15989955
[10] “The essential mitochondrial protein Erv1 cooperates with Mia40 in biogenesis of intermembrane space proteins.”  Rissler M.et.al.   16181637
[11] “Proteomic analysis of the yeast mitochondrial outer membrane reveals accumulation of a subclass of preproteins.”  Zahedi R.P.et.al.   16407407
[12] “A multidimensional chromatography technology for in-depth phosphoproteome analysis.”  Albuquerque C.P.et.al.   18407956
Structure:
2ZXT   3A3C     

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FASTA formatted sequence
1:	MLRNLVVRNA CRNRPSIQVA RGLCRHQTRR LMASSPQFGR NSNQEKTAGF IMGILSMAGA 
61:	LYFIAPNRKP LFASRKVESD KTAEEELSSG GEQSPENEDD NNSKSDENGD DNDSKNDETE 
121:	AGPQLGGDKI GASKVAEDGE LVVLAEEDNK SSEDKDTDES KVSTKDDEQS NEDNATANNQ 
181:	KDENISSENS EENTSDKTLD NNAGSSEKKD PEHSDDEKSQ QGQSDDKTTT EDNNGEEESS 
241:	KKTVSDSENS AKQSESSDEE KEELRKQEEK QMGPTEEEVQ HEGAYNPDTG EINWDCPCLG 
301:	GMAHGPCGEE FKSAFSCFVY SEAEPKGIDC VEKFQHMQDC FRKYPEHYAE QLKETSDDEE 
361:	PQDKVKVNTI ESAPNVSSAK ENAAKKAEQS DVKKEPLNEE SKP