TmAlphaFold Database: Membrane Localization and Evaluation of AlphaFold2 Predicted Alpha-helical Transmembrane Protein Structures

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2022 Nov 1

PMID 36318239

Authors

Laszlo Dobson

Levente I Szekeres

Csongor Gerdan

Tamas Lango

Andras Zeke

Gabor E Tusnady

Affiliations

Soon will be listed here.

Abstract

AI-driven protein structure prediction, most notably AlphaFold2 (AF2) opens new frontiers for almost all fields of structural biology. As traditional structure prediction methods for transmembrane proteins were both complicated and error prone, AF2 is a great help to the community. Complementing the relatively meager number of experimental structures, AF2 provides 3D predictions for thousands of new alpha-helical membrane proteins. However, the lack of reliable structural templates and the fact that AF2 was not trained to handle phase boundaries also necessitates a delicate assessment of structural correctness. In our new database, Transmembrane AlphaFold database (TmAlphaFold database), we apply TMDET, a simple geometry-based method to visualize the likeliest position of the membrane plane. In addition, we calculate several parameters to evaluate the location of the protein into the membrane. This also allows TmAlphaFold database to show whether the predicted 3D structure is realistic or not. The TmAlphaFold database is available at https://tmalphafold.ttk.hu/.

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References

Bowie J . Solving the membrane protein folding problem. Nature. 2005; 438(7068):581-9. DOI: 10.1038/nature04395. View

Dobson L, Remenyi I, Tusnady G . CCTOP: a Consensus Constrained TOPology prediction web server. Nucleic Acids Res. 2015; 43(W1):W408-12. PMC: 4489262. DOI: 10.1093/nar/gkv451. View

Sehnal D, Bittrich S, Deshpande M, Svobodova R, Berka K, Bazgier V . Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res. 2021; 49(W1):W431-W437. PMC: 8262734. DOI: 10.1093/nar/gkab314. View

Lomize M, Pogozheva I, Joo H, Mosberg H, Lomize A . OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res. 2011; 40(Database issue):D370-6. PMC: 3245162. DOI: 10.1093/nar/gkr703. View

Dobson L, Remenyi I, Tusnady G . The human transmembrane proteome. Biol Direct. 2015; 10:31. PMC: 4445273. DOI: 10.1186/s13062-015-0061-x. View

Frishman D, Argos P . Knowledge-based protein secondary structure assignment. Proteins. 1995; 23(4):566-79. DOI: 10.1002/prot.340230412. View

Ruff K, Pappu R . AlphaFold and Implications for Intrinsically Disordered Proteins. J Mol Biol. 2021; 433(20):167208. DOI: 10.1016/j.jmb.2021.167208. View

Altschul S, Gish W, Miller W, Myers E, Lipman D . Basic local alignment search tool. J Mol Biol. 1990; 215(3):403-10. DOI: 10.1016/S0022-2836(05)80360-2. View

Tsirigos K, Peters C, Shu N, Kall L, Elofsson A . The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides. Nucleic Acids Res. 2015; 43(W1):W401-7. PMC: 4489233. DOI: 10.1093/nar/gkv485. View

10.

Lu F, Li S, Jiang Y, Jiang J, Fan H, Lu G . Structure and mechanism of the uracil transporter UraA. Nature. 2011; 472(7342):243-6. DOI: 10.1038/nature09885. View

11.

Ryan E, Marshall A, Magaletti D, Floyd H, Draves K, Olson N . Dendritic cell-associated lectin-1: a novel dendritic cell-associated, C-type lectin-like molecule enhances T cell secretion of IL-4. J Immunol. 2002; 169(10):5638-48. DOI: 10.4049/jimmunol.169.10.5638. View

12.

Tusnady G, Dosztanyi Z, Simon I . TMDET: web server for detecting transmembrane regions of proteins by using their 3D coordinates. Bioinformatics. 2004; 21(7):1276-7. DOI: 10.1093/bioinformatics/bti121. View

13.

Meszaros B, Erdos G, Dosztanyi Z . IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res. 2018; 46(W1):W329-W337. PMC: 6030935. DOI: 10.1093/nar/gky384. View

14.

Wang C, Sun B, Zhang X, Huang X, Zhang M, Guo H . Structural mechanism of the active bicarbonate transporter from cyanobacteria. Nat Plants. 2019; 5(11):1184-1193. DOI: 10.1038/s41477-019-0538-1. View

15.

Wang X, Cheng X, Zhao L, Wang Y, Ye C, Zou X . Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2. Proc Natl Acad Sci U S A. 2021; 118(32). PMC: 8364112. DOI: 10.1073/pnas.2101279118. View

16.

Ge J, Elferich J, Dehghani-Ghahnaviyeh S, Zhao Z, Meadows M, von Gersdorff H . Molecular mechanism of prestin electromotive signal amplification. Cell. 2021; 184(18):4669-4679.e13. PMC: 8674105. DOI: 10.1016/j.cell.2021.07.034. View

17.

Bernhofer M, Rost B . TMbed: transmembrane proteins predicted through language model embeddings. BMC Bioinformatics. 2022; 23(1):326. PMC: 9358067. DOI: 10.1186/s12859-022-04873-x. View

18.

Teufel F, Almagro Armenteros J, Johansen A, Gislason M, Pihl S, Tsirigos K . SignalP 6.0 predicts all five types of signal peptides using protein language models. Nat Biotechnol. 2022; 40(7):1023-1025. PMC: 9287161. DOI: 10.1038/s41587-021-01156-3. View

19.

Klammt C, Maslennikov I, Bayrhuber M, Eichmann C, Vajpai N, Chiu E . Facile backbone structure determination of human membrane proteins by NMR spectroscopy. Nat Methods. 2012; 9(8):834-9. PMC: 3723349. DOI: 10.1038/nmeth.2033. View

20.

Kall L, Sonnhammer E . Reliability of transmembrane predictions in whole-genome data. FEBS Lett. 2002; 532(3):415-8. DOI: 10.1016/s0014-5793(02)03730-4. View