Domain distribution and intrinsic disorder in hubs in the human protein–protein interaction network

Patil, Ashwini; Kinoshita, Kengo; Nakamura, Haruki

doi:10.1002/pro.425

Cited by 60 publications

(61 citation statements)

References 36 publications

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“…Sequence diversity within this domain is observed in only two regions, one of which is the CH1-1 loop, suggesting that it may play a role in the functional diversity of Abs. In addition to its flexibility, the CH1-1 loop is also intrinsically disordered, at least in part, in more than one third of the structures in our dataset, which may suggest the existence of a functional binding site (60). Although the majority of Ab effector functions (e.g., complement activation and interaction with FcRs) are mediated by binding of the Fc, it was suggested that complement binding is also mediated by the CH1-1 loop.…”

Section: Discussionmentioning

confidence: 80%

A Systematic Comparison of Free and Bound Antibodies Reveals Binding-Related Conformational Changes

Sela-Culang

Alon

Ofran

2012

The Journal of Immunology

104

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To study structural changes that occur in Abs upon Ag binding, we systematically compared free and bound structures of all 141 crystal structures of the 49 Abs that were solved in these two forms. We found that many structural changes occur far from the Ag binding site. Some of them may constitute a mechanism for the recently suggested allosteric effects in Abs. Within the binding site itself, CDR-H3 is the only element that shows significant binding-related conformational changes; however, this occurs in only one third of the Abs. Beyond the binding site, Ag binding is associated with changes in the relative orientation of the H and L chains in both the variable and constant domains. An even larger change occurs in the elbow angle between the variable and the constant domains, and it is significantly larger for binding of big Ags than for binding of small ones. The most consistent and substantial conformational changes occur in a loop in the H chain constant domain. This loop is implicated in the interaction between the H and L chains, is often intrinsically disordered, and is involved in complement binding. Hence, we suggest that it may have a role in Ab function. These findings provide structural insight into the recently proposed allosteric effects in Abs.

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Section: Discussionmentioning

confidence: 80%

A Systematic Comparison of Free and Bound Antibodies Reveals Binding-Related Conformational Changes

Sela-Culang

Alon

Ofran

2012

The Journal of Immunology

104

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“…As pointed out above, IDPs and IDRs can readily bind to multiple partners, so based on these observations, we proposed that the special features that enabled the evolution of complex networks containing hubs was IDPs and IDRs 25 . This proposal has been supported by a number of subsequent studies 47,[60][61][62][63][64][65] .…”

Section: Introductionmentioning

confidence: 72%

Molecular recognition features (MoRFs) in three domains of life

et al. 2016

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Intrinsically disordered proteins and protein regions offer numerous advantages in the context of protein-protein interactions when compared to the structured proteins and domains. These advantages include ability to interact with multiple partners, to fold into different conformations when bound to different partners, and to undergo disorder-to-order transitions concomitant with their functional activity. Molecular Recognition Features (MoRFs) are widespread elements located in disordered regions that undergo disorder-to-order transition upon binding to their protein partners. We characterize abundance, composition, and functions of MoRFs and their association with the disordered regions across 868 species spread across Eukaryota, Bacteria and Archaea. We found that although disorder is substantially elevated in Eukaryota, MoRFs have similar abundance and amino acid composition across the three domains of life. The abundance of MoRFs is highly correlated with the amount of intrinsic disorder in Bacteria and Archaea but only modestly correlated in Eukaryota. Proteins with MoRFs have significantly more disorder and MoRFs are present in many disordered regions, with Eukaryota having more MoRF-free disordered regions. MoRF-containing proteins are enriched in the ribosome, nucleus, nucleolus and microtubule and are involved in translation, protein transport, protein folding, and interactions with DNAs. Our insights into the nature and function of MoRFs enhance our understanding of the mechanisms underlying the disorder-to-order transition and protein-protein recognition and interactions. The fMoRFpred method that we used to annotate MoRFs is available at

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“…We further suggested two ways that disorder could be used by hub proteins for binding to multiple partners: (1) One region of disorder could bind to many different partners (one-to-many binding), so the hub protein itself uses disorder for multiple partner binding; and (2) many different regions of disorder could bind to a single partner (many-to-one binding), so the hub protein is structured but binds to many disordered partners via interaction with disorder. 8 Since this initial proposal, we [9][10][11] and many others [12][13][14][15][16][17][18][19][20][21][22] have provided additional evidence that hubs and/or their binding partners are especially enriched in intrinsic disorder, with both the many-to-one and one-to-many processes involving the use of intrinsic disorder.…”

Section: Introductionmentioning

confidence: 95%

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

et al. 2013

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Molecular recognition features (MoRFs) are intrinsically disordered protein regions that bind to partners via disorder-to-order transitions. In one-to-many binding, a single MoRF binds to two or more different partners individually. MoRF-based one-to-many protein-protein interaction (PPI) examples were collected from the Protein Data Bank, yielding 23 MoRFs bound to 2-9 partners, with all pairs of same-MoRF partners having less than 25% sequence identity. Of these, 8 MoRFs were bound to 2-9 partners having completely different folds, whereas 15 MoRFs were bound to 2-5 partners having the same folds but with low sequence identities. For both types of partner variation, backbone and side chain torsion angle rotations were used to bring about the conformational changes needed to enable close fits between a single MoRF and distinct partners. Alternative splicing events (ASEs) and posttranslational modifications (PTMs) were also found to contribute to distinct partner binding. Because ASEs and PTMs both commonly occur in disordered regions, and because both ASEs and PTMs are often tissue-specific, these data suggest that MoRFs, ASEs, and PTMs may collaborate to alter PPI networks in different cell types. These data enlarge the set of carefully studied MoRFs that use inherent flexibility and that also use ASE-based and/or PTM-based surface modifications to enable the same disordered segment to selectively associate with two or more partners. The small number of residues involved in MoRFs and in their modifications by ASEs or PTMs may simplify the evolvability of signaling network diversity.

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Domain distribution and intrinsic disorder in hubs in the human protein–protein interaction network

Cited by 60 publications

References 36 publications

A Systematic Comparison of Free and Bound Antibodies Reveals Binding-Related Conformational Changes

A Systematic Comparison of Free and Bound Antibodies Reveals Binding-Related Conformational Changes

Molecular recognition features (MoRFs) in three domains of life

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

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