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Decomposing the space of protein quaternary structures with the interface fragment pair library.

Xie ZR, Chen J, Zhao Y, Wu Y - BMC Bioinformatics (2015)

Bottom Line: After structural-based clustering, we found that more than 90% of these interface fragment pairs can be represented by a limited number of highly abundant motifs.Our study therefore presents supportive evidences that the space of protein quaternary structures can be represented by the combination of a small set of secondary-structure-based packing at binding interfaces.Finally, after future improvements such as adding sequence profiles, we expect this new library will be useful to predict structures of unknown protein-protein interactions.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY, 10461, USA. Zhong-Ru.Xie@einstein.yu.edu.

ABSTRACT

Background: The physical interactions between proteins constitute the basis of protein quaternary structures. They dominate many biological processes in living cells. Deciphering the structural features of interacting proteins is essential to understand their cellular functions. Similar to the space of protein tertiary structures in which discrete patterns are clearly observed on fold or sub-fold motif levels, it has been found that the space of protein quaternary structures is highly degenerate due to the packing of compact secondary structure elements at interfaces. Therefore, it is necessary to further decompose the protein quaternary structural space into a more local representation.

Results: Here we constructed an interface fragment pair library from the current structure database of protein complexes. After structural-based clustering, we found that more than 90% of these interface fragment pairs can be represented by a limited number of highly abundant motifs. These motifs were further used to guide complex assembly. A large-scale benchmark test shows that the native-like binding is highly likely in the structural ensemble of modeled protein complexes that were built through the library.

Conclusions: Our study therefore presents supportive evidences that the space of protein quaternary structures can be represented by the combination of a small set of secondary-structure-based packing at binding interfaces. Finally, after future improvements such as adding sequence profiles, we expect this new library will be useful to predict structures of unknown protein-protein interactions.

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Related in: MedlinePlus

Similar fragment pairs exist in different domain interactions. Fragment pairs of two helices are located at the interfaces of two different domain interactions in (a) and (b). Two fragments form inter-molecular β-sheet in (c) and (d). One of these two structures is a homo-dimer and the other one is a heterodimer. Finally, similar LL motifs are found in very different binding interfaces, as shown in (e) and (f). The backbones of interacting protein domains are in red and green, while the fragment pair motifs at their interfaces are in yellow and blue with cartoon representation.
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Fig6: Similar fragment pairs exist in different domain interactions. Fragment pairs of two helices are located at the interfaces of two different domain interactions in (a) and (b). Two fragments form inter-molecular β-sheet in (c) and (d). One of these two structures is a homo-dimer and the other one is a heterodimer. Finally, similar LL motifs are found in very different binding interfaces, as shown in (e) and (f). The backbones of interacting protein domains are in red and green, while the fragment pair motifs at their interfaces are in yellow and blue with cartoon representation.

Mentions: Figure 6 illustrates that similar fragment pairs exist in different domain interactions. The backbones of interacting protein domains in the figure are in red and green, while the fragment pair motifs at their interfaces are in yellow and blue with cartoon representation. As shown in Figure 6a and b, fragment pairs of two helices are located at the interfaces of both dimers, while the structures of these two dimers are not identical. Furthermore, two fragments form inter-molecular β-sheet in both Figure 6c and d. One of these two structures, however, is a homo-dimer (Figure 6c) and the other one is a heterodimer (Figure 6d). Finally, similar LL motifs are also found in very different binding interfaces, as shown in Figure 6e and f. These popular fragment pairs indicate biological insights to protein-protein interactions. They reflect specific binding patterns which are significant to the cellular functions of proteins. For instance, death domain is the most important structural module involved in the regulation of apoptosis and inflammation. Packing between helices (Figure 5a and b) is the most common way in death domain induced complex assembly. Moreover, the SS motifs (Figure 5c and d) lead to the formation of intermolecular β-sheet. It is the major driven force of fibrous protein aggregations. Abnormal accumulation of these aggregates, known as amyloid fibrils, in organs may lead to amyloidosis, and may play a role in various neurodegenerative disorders. Finally, fragment pairs involving loops are the most common binding patterns of cell signal transduction, such as the binding motifs found in SH2 or SH3 domains.Figure 6


Decomposing the space of protein quaternary structures with the interface fragment pair library.

Xie ZR, Chen J, Zhao Y, Wu Y - BMC Bioinformatics (2015)

Similar fragment pairs exist in different domain interactions. Fragment pairs of two helices are located at the interfaces of two different domain interactions in (a) and (b). Two fragments form inter-molecular β-sheet in (c) and (d). One of these two structures is a homo-dimer and the other one is a heterodimer. Finally, similar LL motifs are found in very different binding interfaces, as shown in (e) and (f). The backbones of interacting protein domains are in red and green, while the fragment pair motifs at their interfaces are in yellow and blue with cartoon representation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384354&req=5

Fig6: Similar fragment pairs exist in different domain interactions. Fragment pairs of two helices are located at the interfaces of two different domain interactions in (a) and (b). Two fragments form inter-molecular β-sheet in (c) and (d). One of these two structures is a homo-dimer and the other one is a heterodimer. Finally, similar LL motifs are found in very different binding interfaces, as shown in (e) and (f). The backbones of interacting protein domains are in red and green, while the fragment pair motifs at their interfaces are in yellow and blue with cartoon representation.
Mentions: Figure 6 illustrates that similar fragment pairs exist in different domain interactions. The backbones of interacting protein domains in the figure are in red and green, while the fragment pair motifs at their interfaces are in yellow and blue with cartoon representation. As shown in Figure 6a and b, fragment pairs of two helices are located at the interfaces of both dimers, while the structures of these two dimers are not identical. Furthermore, two fragments form inter-molecular β-sheet in both Figure 6c and d. One of these two structures, however, is a homo-dimer (Figure 6c) and the other one is a heterodimer (Figure 6d). Finally, similar LL motifs are also found in very different binding interfaces, as shown in Figure 6e and f. These popular fragment pairs indicate biological insights to protein-protein interactions. They reflect specific binding patterns which are significant to the cellular functions of proteins. For instance, death domain is the most important structural module involved in the regulation of apoptosis and inflammation. Packing between helices (Figure 5a and b) is the most common way in death domain induced complex assembly. Moreover, the SS motifs (Figure 5c and d) lead to the formation of intermolecular β-sheet. It is the major driven force of fibrous protein aggregations. Abnormal accumulation of these aggregates, known as amyloid fibrils, in organs may lead to amyloidosis, and may play a role in various neurodegenerative disorders. Finally, fragment pairs involving loops are the most common binding patterns of cell signal transduction, such as the binding motifs found in SH2 or SH3 domains.Figure 6

Bottom Line: After structural-based clustering, we found that more than 90% of these interface fragment pairs can be represented by a limited number of highly abundant motifs.Our study therefore presents supportive evidences that the space of protein quaternary structures can be represented by the combination of a small set of secondary-structure-based packing at binding interfaces.Finally, after future improvements such as adding sequence profiles, we expect this new library will be useful to predict structures of unknown protein-protein interactions.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY, 10461, USA. Zhong-Ru.Xie@einstein.yu.edu.

ABSTRACT

Background: The physical interactions between proteins constitute the basis of protein quaternary structures. They dominate many biological processes in living cells. Deciphering the structural features of interacting proteins is essential to understand their cellular functions. Similar to the space of protein tertiary structures in which discrete patterns are clearly observed on fold or sub-fold motif levels, it has been found that the space of protein quaternary structures is highly degenerate due to the packing of compact secondary structure elements at interfaces. Therefore, it is necessary to further decompose the protein quaternary structural space into a more local representation.

Results: Here we constructed an interface fragment pair library from the current structure database of protein complexes. After structural-based clustering, we found that more than 90% of these interface fragment pairs can be represented by a limited number of highly abundant motifs. These motifs were further used to guide complex assembly. A large-scale benchmark test shows that the native-like binding is highly likely in the structural ensemble of modeled protein complexes that were built through the library.

Conclusions: Our study therefore presents supportive evidences that the space of protein quaternary structures can be represented by the combination of a small set of secondary-structure-based packing at binding interfaces. Finally, after future improvements such as adding sequence profiles, we expect this new library will be useful to predict structures of unknown protein-protein interactions.

Show MeSH
Related in: MedlinePlus