Structural features for homodimer folding mechanism

Lulu, Sajitha; Suresh, Abishek; Karthikraja, Velmurugan; Arumugam, Mohanapriya; Kayathri, Rajarathinam; Kangueane, Pandjassarame

doi:10.1016/j.jmgm.2009.04.002

Cited by 13 publications

(14 citation statements)

References 11 publications

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“…This analysis is restricted to hetero complexes for the purpose of clarity and comparison with previously known information. It should be noted that homo (identical subunits) dimer complexes stabilized by interfaces with unique characteristics in a completely different platform as described elsewhere [27] is not included in this study.…”

Section: Introductionmentioning

confidence: 99%

Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity

et al. 2017

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Several catalysis, cellular regulation, immune function, cell wall assembly, transport, signaling and inhibition occur through Protein- Protein Interactions (PPI). This is possible with the formation of specific yet stable protein-protein interfaces. Therefore, it is of interest to understand its molecular principles using structural data in relation to known function. Several interface features have been documented using known X-ray structures of protein complexes since 1975. This has improved our understanding of the interface using structural features such as interface area, binding energy, hydrophobicity, relative hydrophobicity, salt bridges and hydrogen bonds. The strength of binding between two proteins is dependent on interface size (number of residues at the interface) and thus its corresponding interface area. It is known that large interfaces have high binding energy (sum of (van der Waals) vdW, H-bonds, electrostatics). However, the selective role played by each of these energy components and more especially that of vdW is not explicitly known. Therefore, it is important to document their individual role in known protein-protein structural complexes. It is of interest to relate interface size with vdW, H-bonds and electrostatic interactions at the interfaces of protein structural complexes with known function using statistical and multiple linear regression analysis methods to identify the prominent force. We used the manually curated non-redundant dataset of 278 hetero-dimeric protein structural complexes grouped using known functions by Sowmya et al. (2015) to gain additional insight to this phenomenon using a robust inter-atomic non-covalent interaction analyzing tool PPCheck (Anshul and Sowdhamini, 2015). This dataset consists of obligatory (enzymes, regulator, biological assembly), immune and nonobligatory (enzyme and regulator inhibitors) complexes. Results show that the total binding energy is more for large interfaces. However, this is not true for its individual energy factors. Analysis shows that vdW energies contribute to about 75% ± 11% on average among all complexes and it also increases with interface size (r2 ranging from 0.67 to 0.89 with p<0.01) at 95% confidence limit irrespective of molecular function. Thus, vdW is both dominant and proportional at the interface independent of molecular function. Nevertheless, H bond energy contributes to 15% ± 6.5% on average in these complexes. It also moderately increases with interface size (r2 ranging from 0.43 to 0.61 with p<0.01) only among obligatory and immune complexes. Moreover, there is about 11.3% ± 8.7% contribution by electrostatic energy. It increases with interface size specifically among non-obligatory regulator-inhibitors (r2 = 0.44). It is implied that both H-bonds and electrostatics are neither dominant nor proportional at the interface. Nonetheless, their presence cannot be ignored in binding. Therefore, H-bonds and (or) electrostatic energy having specific role for improved stability in complexes is implied. Thus, vdW is commo...

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Section: Introductionmentioning

confidence: 99%

Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity

et al. 2017

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“…The relationship between homo-dimer folding mechanism and known homodimers structures have been investigated in recent studies using structural datasets [3–9]. Neet and Timm (1994) reviewed unfolding data for 17 homodimers and documented some homodimers having 3S mechanism while others with 2S mechanism [2].…”

Section: Discussionmentioning

confidence: 99%

“…Li and colleagues (2005) used 41 homodimer structures and showed that small proteins with large interface area and high interface hydrophobicity are 2S and 3S are large proteins with small interface area and low interface hydrophobicity. [8] Lulu and colleagues (2009) showed that interface to total (I/T) residues ratio is large for 2S than 3SMI and 3SDI in a dataset of 42 homodimers [9]. Thus, these studies provide structural insight to homodimers folding mechanism using structural data.…”

Section: Discussionmentioning

confidence: 99%

“…However, 3S are large proteins with small interface area and low interface hydrophobicity (60%). Lulu and colleagues documented structural features to discriminate 2S and 3S homodimers in a dataset of 42 structures [9]. Here, we describe the analysis of 47 homodimers (twenty eight 2S, twelve 3SMI and seven 3SDI) to examine the types of inter subunit interactions at their interfaces.…”

Section: Introductionmentioning

confidence: 99%

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Types of interfaces for homodimer folding and binding

Karthikraja¹,

Suresh²,

Lulu³

et al. 2009

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Homodimers have a role in catalysis and regulation through the formation of stable interfaces. These interfaces are formed through different folding mechanisms such as 2-state without stable intermediate (2S), 3-state with monomer intermediate (3SMI) and 3-state with dimer intermediate (3SDI). Therefore, it is of interest to understand folding mechanism using structural features at the interfaces. Several studies have documented the significance of structural features for the understanding of homodimer folding mechanisms. However, the known features provide limited information for understanding homodimer folding mechanisms. Hence, we created an extended dataset of 47 homodimers (twenty eight 2S, twelve 3SMI and seven 3SDI) to examine the types of interfaces in protein homodimers. 2S are usually small sized, 3SMI are often medium sized and 3SDI often exist as large sized proteins. The ratio of interface to total (I/T) residue is large in 2S and small in 3SMI and 3SDI. Hence, we used I/T measure to group 2S, 3SMI and 3SDI into categories with large I/T (≫ 50%), moderate I/T (50 - 25%) and small I/T (≪ 25%) interfaces. The grouping is further sub-grouped based on the type of physical interaction visualized at the interface using representations in two dimensions (2D). 2D representation of the interface shows eight different forms of interactions in these homodimers. 2S homodimers frequently have large I/T and thus, utilize the entire protein structure in the formation of the interface where the individual subunits are heavily inter communicated with each other. This is not true in the case of 3SMI and 3SDI. 3SMI subunits usually interact with each other at the interface with a gentle touch-like contact and hence, they have low I/T ratio. 3SDI are often quite different in interaction compared to 3SMI and their subunits do deeply interact at the interface with only one part of the surface and hence also having low I/T ratio.

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“…It should be stated that these studies use datasets consisting of both heterodimers and homodimers. The formation of homodimers and their folding through 2-state (2S - without intermediate) and 3-state (3S - with stable intermediate) mechanisms is distinct from that of heterodimers [20]. Therefore, it is our interest here, to study and understand heterodimer complexes only, using interface residue types.…”

Section: Introductionmentioning

confidence: 99%

Insights from the structural analysis of protein heterodimer interfaces

Sowmya¹,

Anita²,

Kangueane³

2011

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Protein heterodimer complexes are often involved in catalysis, regulation, assembly, immunity and inhibition. This involves the formation of stable interfaces between the interacting partners. Hence, it is of interest to describe heterodimer interfaces using known structural complexes. We use a non-redundant dataset of 192 heterodimer complex structures from the protein databank (PDB) to identify interface residues and describe their interfaces using amino-acids residue property preference. Analysis of the dataset shows that the heterodimer interfaces are often abundant in polar residues. The analysis also shows the presence of two classes of interfaces in heterodimer complexes. The first class of interfaces (class A) with more polar residues than core but less than surface is known. These interfaces are more hydrophobic than surfaces, where protein-protein binding is largely hydrophobic. The second class of interfaces (class B) with more polar residues than core and surface is shown. These interfaces are more polar than surfaces, where binding is mainly polar. Thus, these findings provide insights to the understanding of protein-protein interactions.

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Structural features for homodimer folding mechanism

Cited by 13 publications

References 11 publications

Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity

Protein-protein interfaces are vdW dominant with selective H-bonds and (or) electrostatics towards broad functional specificity

Types of interfaces for homodimer folding and binding

Insights from the structural analysis of protein heterodimer interfaces

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