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Intrinsic disorder and protein multibinding in domain, terminal, and linker regions.

ABSTRACT: Intrinsic disorder is believed to contribute to the ability of some proteins to interact with multiple partners which is important for protein functional promiscuity and regulation of the cross-talk between pathways. To better understand the mechanisms of molecular recognition through disordered regions, here, we systematically investigate the coupling between disorder and binding within domain families in a structure interaction network and in terminal and inter-domain linker regions. We showed that the canonical domain-domain interaction model should take into account contributions of N- and C-termini and inter-domain linkers, which may form all or part of the binding interfaces. For the majority of proteins, binding interfaces on domain and terminal regions were predicted to be less disordered than non-interface regions. Analysis of all domain families revealed several exceptions, such as kinases, DNA/RNA binding proteins, certain enzymes, and regulatory proteins, which are candidates for disorder-to-order transitions that can occur upon binding. Domain interfaces that bind single or multiple partners do not exhibit significant difference in disorder content if normalized by the number of interactions. In general, protein families with more diverse interactions exhibit less average disorder over all members of the family. Our results shed light on recent controversies regarding the relationship between disorder and binding of multiple partners at common interfaces. In particular, they support the hypothesis that protein domains with many interacting partners should have a pleiotropic effect on functional pathways and consequently might be more constrained in evolution.

SUBMITTER: Fong JH

PROVIDER: S-EPMC2955455 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Intrinsic disorder and protein multibinding in domain, terminal, and linker regions.

Fong Jessica H JH Panchenko Anna R AR

Molecular bioSystems 20100611 10

Intrinsic disorder is believed to contribute to the ability of some proteins to interact with multiple partners which is important for protein functional promiscuity and regulation of the cross-talk between pathways. To better understand the mechanisms of molecular recognition through disordered regions, here, we systematically investigate the coupling between disorder and binding within domain families in a structure interaction network and in terminal and inter-domain linker regions. We showed ...[more]

PMID: 20544079

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Project description:The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R?W, R?C, E?K, R?H, R?Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased ?-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.

Dataset Information

Intrinsic disorder and protein multibinding in domain, terminal, and linker regions.

Publications

Intrinsic disorder and protein multibinding in domain, terminal, and linker regions.

Similar Datasets

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