“Multiple partial recognitions in dynamic equilibrium” in the binding sites of proteins form the molecular basis of promiscuous recognition of structurally diverse ligands
Promiscuous recognition of ligands by proteins is as important as strict recognition in numerous biological processes. In living cells, many short, linear amino acid motifs function as targeting signals in proteins to specify the final destination of the protein transport. In general, the target signal is defined by a consensus sequence containing wild-characters, and hence represented by diverse amino acid sequences. The classical lock-and-key or induced-fit/conformational selection mechanism may not cover all aspects of the promiscuous recognition. On the basis of our crystallographic and NMR studies on the mitochondrial Tom20 protein–presequence interaction, we proposed a new hypothetical mechanism based on “a rapid equilibrium of multiple states with partial recognitions”. This dynamic, multiple recognition mode enables the Tom20 receptor to recognize diverse mitochondrial presequences with nearly equal affinities. The plant Tom20 is evolutionally unrelated to the animal Tom20 in our study, but is a functional homolog of the animal/fungal Tom20. NMR studies by another research group revealed that the presequence binding by the plant Tom20 was not fully explained by simple interaction modes, suggesting the presence of a similar dynamic, multiple recognition mode. Circumstantial evidence also suggested that similar dynamic mechanisms may be applicable to other promiscuous recognitions of signal peptides by the SRP54/Ffh and SecA proteins.
KeywordsMitochondrial presequence Promiscuous recognition Signal sequence Targeting signal Tom20
Multiple partial recognition in dynamic equilibrium
Nuclear Overhauser effect
Translocase of the inner mitochondrial membrane
Translocase of the outer mitochondrial membrane
20-kDa subunit of the TOM complex
Paramagnetic relaxation enhancement
This review is the achievement of our long-term research project for more than 20 years, conducted at the Biomolecular Engineering Research Institute with Drs. Yoshito Abe and Takanori Muto, and at the Medical Institute of Bioregulation, Kyushu University, with Drs. Takayuki Obita, Takashi Saitoh, Toyoyuki Ose, Nobuo Maita, Reiko Kojima, Mayumi Igura, Rei Matsuoka, and Atsushi Shimada, Mr. Keisei Izumi, and Ms. Han Xiling. We thank Professor Toshiya Endo (Kyoto Sangyo University) for fruitful discussions on the biochemical functions of the TOM and TIM proteins, and Drs. Yasuaki Komuro and Yuji Sugita (RIKEN Advanced Science Institute), and Dr. Naoyuki Miyashita (RIKEN Quantitative Biology Center) for their MD calculations and stimulating discussions.
Compliance with ethical standards
Conflict of interest
Daisuke Kohda declares that the author has no conflicts of interest.
This article does not contain any studies with human participants or animals performed by the author.
- Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395–447. https://doi.org/10.1146/annurev.biochem.72.121801.161800 CrossRefPubMedGoogle Scholar
- Fischer E (1894) Einfluss der Configuration auf die Wirkung der Enzyme. Ber Dtsch Chem Ges 27:2984–2993Google Scholar
- Rapoport TA, Li L, Park E (2017) Structural and mechanistic insights into protein translocation. Annu Rev Cell Dev Biol 33:369–390. https://doi.org/10.1146/annurev-cellbio-100616-060439 CrossRefPubMedGoogle Scholar
- von Heijne G (1986) Mitochondrial targeting sequences may form amphiphilic helices. EMBO J 5:1335–1342Google Scholar
- Voorhees RM, Hegde RS (2015) Structures of the scanning and engaged states of the mammalian SRP–ribosome complex. Elife 4. https://doi.org/10.7554/eLife.07975
- Yamamoto H, Itoh N, Kawano S, Yatsukawa Y, Momose T, Makio T, Matsunaga M, Yokota M, Esaki M, Shodai T, Kohda D, Hobbs AE, Jensen RE, Endo T (2011) Dual role of the receptor Tom20 in specificity and efficiency of protein import into mitochondria. Proc Natl Acad Sci U S A 108:91–96. https://doi.org/10.1073/pnas.1014918108 CrossRefPubMedGoogle Scholar