Analysis of Molecular Recognition Features (MoRFs)

Mohan, Amrita; Oldfield, Christopher J.; Radivojac, Predrag; Vacic, Vladimir; Cortese, Marc S.; Dunker, A. Keith; Uversky, Vladimir N.

doi:10.1016/j.jmb.2006.07.087

Cited by 691 publications

(704 citation statements)

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“…The previous analysis showed that MoRFs have amino acid compositions much more similar to disordered proteins than to ordered proteins. 33 The current analysis shows that MoRF interfaces generally have compositions that are very different from the compositions of the overall surfaces of monomers (Figure 3), where MoRFs are generally enriched in residues that are typically buried within structured proteins and depleted in residues that are typically exposed. These compositional results seemingly conflict with the high degree of surface exposure of MoRF interface residues ( Figures 4E and F), which is likely an indication of a high propensity of these segments to form complexes and thereby bury these residues.…”

Section: Comparative Interface Featuresmentioning

confidence: 75%

“…33 The ability of α-MoRFs to fold upon interaction with binding partners was illustrated by several exemplifying cases described in our recent paper detailing the development of a preliminary α-MoRF predictor. 32 …”

Section: Binding Induced Folding Of Morfsmentioning

confidence: 99%

“…25 The advantages of IDPs in this role are many, including the decoupling of specificity and affinity, 32 the ability to recognize multiple partners through adoption of different conformations, 33 and faster on-rates 34 due perhaps to the fly-casting 35 or fishing 36 mechanism. Clearly, the current approach to the computational unbound-unbound problem is intractable for IDPs and, given their relevance to a broad class of interaction-mediated signaling events, new methods are needed for prediction of the interaction complexes of IDPs.…”

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Characterization of Molecular Recognition Features, MoRFs, and Their Binding Partners

et al. 2007

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Molecular Recognition Features (MoRFs) are short, interaction-prone segments of protein disorder that undergo disorder-to-order transitions upon specific binding, representing a specific class of intrinsically disordered regions that exhibit molecular recognition and binding functions. MoRFs are common in various proteomes and occupy a unique structural and functional niche in which function is a direct consequence of intrinsic disorder. Example MoRFs collected from the Protein Data Bank (PDB) have been divided into three subtypes according to their structures in the bound state: α-MoRFs form α-helices, β-MoRFs form β-strands, and ι-MoRFs form structures without a regular pattern of backbone hydrogen bonds. These example MoRFs were indicated to be intrinsically disordered in the absence of their binding partners by several criteria. In this study we used several geometric and physiochemical criteria to examine the properties of 62 α-, 20 β-and 176 ι-MoRF complex structures. Interface residues were examined by calculating differences in accessible surface area between the complex and isolated monomers. The compositions and physiochemical properties of MoRF and MoRF partner interface residues were compared to the interface residues of homodimers, heterodimers, and antigen-antibody complexes. Our analysis indicates that there are significant differences in residue composition and several geometric and physicochemical properties that can be used to discriminate, with a high degree of accuracy, between various interfaces in protein interaction datasets. Implications of these findings for the development of MoRF-partner interaction predictors are discussed. In addition, structural changes upon MoRF-to-partner complex formation were examined for several illustrative examples. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein-protein interaction sites have been intensively analyzed by different researchers to understand the molecular determinants of protein recognition and to identify specific characteristics of protein-protein interfaces. 1-18 Different aspects of interaction sites, including residue propensities, residue pairing preferences, hydrophobicity, size, shape, solvent accessibility, and hydrogen bond protection, have all been examined. Although each of these parameters provides some information indicative of protein-protein interaction sites, none of them perfectly differentiates interaction sites from noninteracting protein surfaces. Protein interaction sites have been observed to be hydrophobic, planar, globular and protruding. 1, 2, 4, 8, 9, 16 Furthermore, interfaces in different types of even the simplest protein complexes (e.g., homodimers, heterodimers) have different properties 9, 11, 15 . Homocomplexes are often permanent and optimized, whereas many heterocomplexes are nonobligatory, associating and disassociating according to the environmental or external factors and involve proteins that must also exist independently. 9 Subunit interfaces in stable oligomer...

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Section: Comparative Interface Featuresmentioning

confidence: 75%

Section: Binding Induced Folding Of Morfsmentioning

confidence: 99%

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confidence: 99%

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Characterization of Molecular Recognition Features, MoRFs, and Their Binding Partners

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“…55,56 Therefore, a large number of theoretical 55,57 and experimental studies 14,18,[58][59][60][61] of IDPs has focused on identifying elements of partially formed secondary structure, particularly a-helices. In experimental studies trying to identify partially formed helices, it is desirable to work under conditions where the helical elements have the highest population.…”

Section: Discussionmentioning

confidence: 99%

Temperature‐dependent structural changes in intrinsically disordered proteins: Formation of α‒helices or loss of polyproline II?

Kjærgaard¹,

Nørholm²,

et al. 2010

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Structural characterization of intrinsically disordered proteins (IDPs) is mandatory for deciphering their potential unique physical and biological properties. A large number of circular dichroism (CD) studies have demonstrated that a structural change takes place in IDPs with increasing temperature, which most likely reflects formation of transient a-helices or loss of polyproline II (PPII) content. Using three IDPs, ACTR, NHE1, and Spd1, we show that the temperature-induced structural change is common among IDPs and is accompanied by a contraction of the conformational ensemble. This phenomenon was explored at residue resolution by multidimensional NMR spectroscopy. Intrinsic chemical shift referencing allowed us to identify regions of transiently formed helices and their temperature-dependent changes in helicity. All helical regions were found to lose rather than gain helical structures with increasing temperature, and accordingly these were not responsible for the change in the CD spectra. In contrast, the nonhelical regions exhibited a general temperature-dependent structural change that was independent of long-range interactions. The temperature-dependent CD spectroscopic signature of IDPs that has been amply documented can be rationalized to represent redistribution of the statistical coil involving a general loss of PPII conformations.Keywords: intrinsically disordered protein (IDP); transient secondary structure; temperature dependence; polyproline II; circular dichroism (CD); nuclear magnetic resonance spectroscopy (NMR); sodium-proton (Na1/H1) exchanger 1 (NHE1); S-phase delayed 1 (Spd1); activator for thyroid hormone and retinoid receptors (ACTR) Abbreviations: ACTR, activator for thyroid hormone and retinoid receptors; CBP, CREB-binding protein; CD, circular dichroism; IDP, intrinsically disordered protein; NCBD, nuclear coactivator binding domain; NHE1cdt, sodium-proton (Na þ /H þ ) exchanger 1 C-terminal distal tail; NMR, nuclear magnetic resonance; PPII, polyproline II; RDC, residual dipolar coupling; SAXS, small-angle X-ray scattering; Spd1, S-phase delayed 1.

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“…From studies of other systems, it has become apparent that, despite the lack of a fixed three-dimensional structure, disordered proteins are often involved in key cellular processes such as signal transduction and stabilization of both proteins and RNA (Tompa, 2002;Dyson and Wright, 2005;Fink, 2005;Radivojac et al, 2007;Dunker et al, 2008;Uversky and Dunker, 2010). Binding of a disordered protein typically induces folding and activation (Mohan et al, 2006;Tompa and Fuxreiter, 2008;Wright and Dyson, 2009). However, there are also examples of binding without an appreciable degree of folding, or just local secondary-structure formation, for example, the binding of disordered T cell receptors to lipid vesicles (Sigalov and Hendricks, 2009) and Cdc4 binding to Sic1 (Borg et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

et al. 2011

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Dehydrins are intrinsically disordered plant proteins whose expression is upregulated under conditions of desiccation and cold stress. Their molecular function in ensuring plant survival is not yet known, but several studies suggest their involvement in membrane stabilization. The dehydrins are characterized by a broad repertoire of conserved and repetitive sequences, out of which the archetypical K-segment has been implicated in membrane binding. To elucidate the molecular mechanism of these K-segments, we examined the interaction between lipid membranes and a dehydrin with a basic functional sequence composition: Lti30, comprising only K-segments. Our results show that Lti30 interacts electrostatically with vesicles of both zwitterionic (phosphatidyl choline) and negatively charged phospholipids (phosphatidyl glycerol, phosphatidyl serine, and phosphatidic acid) with a stronger binding to membranes with high negative surface potential. The membrane interaction lowers the temperature of the main lipid phase transition, consistent with Lti30's proposed role in cold tolerance. Moreover, the membrane binding promotes the assembly of lipid vesicles into large and easily distinguishable aggregates. Using these aggregates as binding markers, we identify three factors that regulate the lipid interaction of Lti30 in vitro: (1) a pH dependent His on/off switch, (2) phosphorylation by protein kinase C, and (3) reversal of membrane binding by proteolytic digest.

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Analysis of Molecular Recognition Features (MoRFs)

Cited by 691 publications

References 99 publications

Characterization of Molecular Recognition Features, MoRFs, and Their Binding Partners

Characterization of Molecular Recognition Features, MoRFs, and Their Binding Partners

Temperature‐dependent structural changes in intrinsically disordered proteins: Formation of α‒helices or loss of polyproline II?

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

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