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Quaternary structure predictions of transmembrane proteins starting from the monomer: a docking-based approach.

Casciari D, Seeber M, Fanelli F - BMC Bioinformatics (2006)

Bottom Line: We introduce a computational protocol for effective predictions of the supramolecular organization of integral transmembrane proteins, starting from the monomer.With this approach, knowledge about the oligomerization status of the protein is required neither for improving sampling nor for the filtering step.Collectively, the results of this study emphasize the effectiveness of the prediction protocol that will be extensively challenged in quaternary structure predictions of other integral membrane proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, Dulbecco Telethon Institute, University of Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy. casciari.daniele@unimo.it

ABSTRACT

Background: We introduce a computational protocol for effective predictions of the supramolecular organization of integral transmembrane proteins, starting from the monomer. Despite the demonstrated constitutive and functional importance of supramolecular assemblies of transmembrane subunits or proteins, effective tools for structure predictions of such assemblies are still lacking. Our computational approach consists in rigid-body docking samplings, starting from the docking of two identical copies of a given monomer. Each docking run is followed by membrane topology filtering and cluster analysis. Prediction of the native oligomer is therefore accomplished by a number of progressive growing steps, each made of one docking run, filtering and cluster analysis. With this approach, knowledge about the oligomerization status of the protein is required neither for improving sampling nor for the filtering step. Furthermore, there are no size-limitations in the systems under study, which are not limited to the transmembrane domains but include also the water-soluble portions.

Results: Benchmarks of the approach were done on ten homo-oligomeric membrane proteins with known quaternary structure. For all these systems, predictions led to native-like quaternary structures, i.e. with Calpha-RMSDs lower than 2.5 A from the native oligomer, regardless of the resolution of the structural models.

Conclusion: Collectively, the results of this study emphasize the effectiveness of the prediction protocol that will be extensively challenged in quaternary structure predictions of other integral membrane proteins.

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Related in: MedlinePlus

Native and best native-like structures of pentameric MscL. The best predicted native-like pentamer (violet color) is the one encoded as A-Bs8-Cs1-Ds1-Es6 (see Table 1 and Figure 7). The description of this figure is like that of Figure 2.
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Figure 3: Native and best native-like structures of pentameric MscL. The best predicted native-like pentamer (violet color) is the one encoded as A-Bs8-Cs1-Ds1-Es6 (see Table 1 and Figure 7). The description of this figure is like that of Figure 2.

Mentions: Benchmarks of the approach were first carried out on the tetrameric KcsA potassium channel H+ gated (384 amino acids, PDB code: 1BL8; Figure 2) [25], pentameric MscL and eptameric MscS mechanosensitive channels (540 amino acids, PDB code: 1MSL, Figure 3[26], and 1771 amino acids, PDB code: 1MXM, Figure 4) [27], respectively), and trimeric BRD (698 amino acids, PDB code: 1BRR; Figure 5) [2]. Selection of these supramolecular systems followed an accurate inspection of the database of Membrane Protein structures from White's laboratory [1]. The selected proteins, indeed, fulfilled at best the following requirements: (a) the biological unit is a homo-oligomer; (b) the asymmetric crystallographic unit contains the biological unit; (c) the monomers in the biological unit are α-helical TM proteins; and (d) significant structural diversity exists among the selected oligomers concerning oligomeric order, architecture and extension of the intracellular and extracellular domains. Successively, benchmarks have been extended to a number of homo-oligomeric transmembrane proteins, selected from the same database, for which the asymmetric unit is constituted by the monomer. They include a dimer, i.e. the membrane spanning region of the BtuCD Vitamin B12 Transporter (648 amino acids, PDB code: 1L7V) [28]; trimers like the AmtB ammonia channel (1146 amino acids, PDB code: 1U77) [29] and the AcrB bacterial multi-drug efflux transporter (3108 amino acids, PDB code: 1IWG); and tetramers like the AQP1 aquaporin water channel (996 amino acids, PDB code: 1J4N) [30], the GlpF glycerol facilitator channel (1016 amino acids, PDB code: 1FX8) [31], and the KirBac1 Inward-Rectifier Potassium channel (1032 amino acids, PDB code: 1P7B) [32].


Quaternary structure predictions of transmembrane proteins starting from the monomer: a docking-based approach.

Casciari D, Seeber M, Fanelli F - BMC Bioinformatics (2006)

Native and best native-like structures of pentameric MscL. The best predicted native-like pentamer (violet color) is the one encoded as A-Bs8-Cs1-Ds1-Es6 (see Table 1 and Figure 7). The description of this figure is like that of Figure 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1590055&req=5

Figure 3: Native and best native-like structures of pentameric MscL. The best predicted native-like pentamer (violet color) is the one encoded as A-Bs8-Cs1-Ds1-Es6 (see Table 1 and Figure 7). The description of this figure is like that of Figure 2.
Mentions: Benchmarks of the approach were first carried out on the tetrameric KcsA potassium channel H+ gated (384 amino acids, PDB code: 1BL8; Figure 2) [25], pentameric MscL and eptameric MscS mechanosensitive channels (540 amino acids, PDB code: 1MSL, Figure 3[26], and 1771 amino acids, PDB code: 1MXM, Figure 4) [27], respectively), and trimeric BRD (698 amino acids, PDB code: 1BRR; Figure 5) [2]. Selection of these supramolecular systems followed an accurate inspection of the database of Membrane Protein structures from White's laboratory [1]. The selected proteins, indeed, fulfilled at best the following requirements: (a) the biological unit is a homo-oligomer; (b) the asymmetric crystallographic unit contains the biological unit; (c) the monomers in the biological unit are α-helical TM proteins; and (d) significant structural diversity exists among the selected oligomers concerning oligomeric order, architecture and extension of the intracellular and extracellular domains. Successively, benchmarks have been extended to a number of homo-oligomeric transmembrane proteins, selected from the same database, for which the asymmetric unit is constituted by the monomer. They include a dimer, i.e. the membrane spanning region of the BtuCD Vitamin B12 Transporter (648 amino acids, PDB code: 1L7V) [28]; trimers like the AmtB ammonia channel (1146 amino acids, PDB code: 1U77) [29] and the AcrB bacterial multi-drug efflux transporter (3108 amino acids, PDB code: 1IWG); and tetramers like the AQP1 aquaporin water channel (996 amino acids, PDB code: 1J4N) [30], the GlpF glycerol facilitator channel (1016 amino acids, PDB code: 1FX8) [31], and the KirBac1 Inward-Rectifier Potassium channel (1032 amino acids, PDB code: 1P7B) [32].

Bottom Line: We introduce a computational protocol for effective predictions of the supramolecular organization of integral transmembrane proteins, starting from the monomer.With this approach, knowledge about the oligomerization status of the protein is required neither for improving sampling nor for the filtering step.Collectively, the results of this study emphasize the effectiveness of the prediction protocol that will be extensively challenged in quaternary structure predictions of other integral membrane proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Chemistry, Dulbecco Telethon Institute, University of Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy. casciari.daniele@unimo.it

ABSTRACT

Background: We introduce a computational protocol for effective predictions of the supramolecular organization of integral transmembrane proteins, starting from the monomer. Despite the demonstrated constitutive and functional importance of supramolecular assemblies of transmembrane subunits or proteins, effective tools for structure predictions of such assemblies are still lacking. Our computational approach consists in rigid-body docking samplings, starting from the docking of two identical copies of a given monomer. Each docking run is followed by membrane topology filtering and cluster analysis. Prediction of the native oligomer is therefore accomplished by a number of progressive growing steps, each made of one docking run, filtering and cluster analysis. With this approach, knowledge about the oligomerization status of the protein is required neither for improving sampling nor for the filtering step. Furthermore, there are no size-limitations in the systems under study, which are not limited to the transmembrane domains but include also the water-soluble portions.

Results: Benchmarks of the approach were done on ten homo-oligomeric membrane proteins with known quaternary structure. For all these systems, predictions led to native-like quaternary structures, i.e. with Calpha-RMSDs lower than 2.5 A from the native oligomer, regardless of the resolution of the structural models.

Conclusion: Collectively, the results of this study emphasize the effectiveness of the prediction protocol that will be extensively challenged in quaternary structure predictions of other integral membrane proteins.

Show MeSH
Related in: MedlinePlus