Order, Disorder, and Everything in Between

DeForte, Shelly; Uversky, Vladimir N.

doi:10.3390/molecules21081090

Cited by 78 publications

(77 citation statements)

References 112 publications

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“…In agreement with this, our bioinformatics analysis predicts structural elements in Lmod2, which are characterised by relatively large disorder probability, characteristic for intrinsically disordered protein regions (IDRs) (disorder probability > 0.5, Fig 2A) [39–41]. Rattus norvegicus leiomodin2 contains three tryptophans (W73, W386 and W404), which are located in segments with high predicted disorder (Fig 2A).…”

Section: Resultssupporting

confidence: 64%

Cardiac leiomodin2 binds to the sides of actin filaments and regulates the ATPase activity of myosin

et al. 2017

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Leiomodin proteins are vertebrate homologues of tropomodulin, having a role in the assembly and maintenance of muscle thin filaments. Leiomodin2 contains an N-terminal tropomodulin homolog fragment including tropomyosin-, and actin-binding sites, and a C-terminal Wiskott-Aldrich syndrome homology 2 actin-binding domain. The cardiac leiomodin2 isoform associates to the pointed end of actin filaments, where it supports the lengthening of thin filaments and competes with tropomodulin. It was recently found that cardiac leiomodin2 can localise also along the length of sarcomeric actin filaments. While the activities of leiomodin2 related to pointed end binding are relatively well described, the potential side binding activity and its functional consequences are less well understood. To better understand the biological functions of leiomodin2, in the present work we analysed the structural features and the activities of Rattus norvegicus cardiac leiomodin2 in actin dynamics by spectroscopic and high-speed sedimentation approaches. By monitoring the fluorescence parameters of leiomodin2 tryptophan residues we found that it possesses flexible, intrinsically disordered regions. Leiomodin2 accelerates the polymerisation of actin in an ionic strength dependent manner, which relies on its N-terminal regions. Importantly, we demonstrate that leiomodin2 binds to the sides of actin filaments and induces structural alterations in actin filaments. Upon its interaction with the filaments leiomodin2 decreases the actin-activated Mg2+-ATPase activity of skeletal muscle myosin. These observations suggest that through its binding to side of actin filaments and its effect on myosin activity leiomodin2 has more functions in muscle cells than it was indicated in previous studies.

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Section: Resultssupporting

confidence: 64%

Cardiac leiomodin2 binds to the sides of actin filaments and regulates the ATPase activity of myosin

et al. 2017

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“…Contrary to this deterministic interpretation, it is now well established that proteins need not always be folded to remain functional . A large fraction of the proteome across all three kingdoms is composed of intrinsically disordered proteins (IDPs) that, by definition, are ensembles of polymorphic conformers lacking rigid three‐dimensional structure . IDPs and segments within ordered proteins constituting intrinsically disordered regions (IDRs) are characterized by a combination of low mean hydrophobicity and relatively high net charge, important prerequisites for the absence of three‐dimensional structure in proteins under physiological conditions .…”

Section: Introductionmentioning

confidence: 99%

Structural metamorphism and polymorphism in proteins on the brink of thermodynamic stability

Kulkarni

Solomon

et al. 2018

Protein Science

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The classical view of the structure-function paradigm advanced by Anfinsen in the 1960s is that a protein's function is inextricably linked to its three-dimensional structure and is encrypted in its amino acid sequence. However, it is now known that a significant fraction of the proteome consists of intrinsically disordered proteins (IDPs). These proteins populate a polymorphic ensemble of conformations rather than a unique structure but are still capable of performing biological functions. At the boundary, between well-ordered and inherently disordered states are proteins that are on the brink of stability, either weakly stable ordered systems or disordered but on the verge of being stable. In such marginal states, even relatively minor changes can significantly alter the energy landscape, leading to large-scale conformational remodeling. Some proteins on the edge of stability are metamorphic, with the capacity to switch from one fold topology to another in response to an environmental trigger (e.g., pH, temperature/salt, redox). Many IDPs, on the other hand, are marginally unstable such that small perturbations (e.g., phosphorylation, ligands) tip the balance over to a range of ordered, partially ordered, or even more disordered states. In general, the structural transitions described by metamorphic fold switches and polymorphic IDPs possess a number of common features including low or diminished stability, large-scale conformational changes, critical disordered regions, latent or attenuated binding sites, and expansion of function. We suggest that these transitions are, therefore, conceptually and mechanistically analogous, representing adjacent regions in the continuum of order/disorder transitions.

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“…It has been already shown that hub complexes are essential for any living organism and the deletion of a hub is fatal [95]. Besides, several IDPs involved in human pathogeneses are also hubs and examples of these disordered hubs with hundreds of protein partners are p53, α-synuclein, BRCA1, XPA, p21, p27, estrogen receptor and many others [93,94]. There are also IDPs capable of forming protein complexes known as "fuzzy" where they can adopt more than one conformation within the same partner, in a dynamic or static way [96,97].…”

Section: Cryptococcal Meningitismentioning

confidence: 99%

“…At this point is important to emphasize that to be an IDPs does not mean to be unfolded or to exist as an extended theoretical random coil. The IDP structure is not a random organization in solution and that is why only the term IDPs will be used in this thesis instead of other nomenclatures, such as intrinsically unfolded proteins, natively unfolded or even loopy [94] A great number of IDPs are well known to be structurally promiscuous, positioned at the center of the cell interactome, where they act as hubs for interactions with multiple protein partners [90]. The disordered-to-order transition is probably a unique characteristic of IDPs, allowing them to adapt to several different situations [90,93] and is what usually allow these hubs to be so promiscuous for the protein-protein interaction [93].…”

Section: Cryptococcal Meningitismentioning

confidence: 99%

“…Figure 6 shows some of the functions already associated with IDPs and well-folded protein, where we can clearly observe that many of them cannot be described without the notion of disordered structure. For more details about this fascinated world of IDPs, there are a great number of excellent revisions in the literature [90,91,94,98] and books devoted only to this class of proteins [99].…”

Section: Cryptococcal Meningitismentioning

confidence: 99%

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Structural and dynamic characterization of the Golgi Reassembly and Stacking Protein (GRASP) in solution

Mendes¹

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Order, Disorder, and Everything in Between

Cited by 78 publications

References 112 publications

Cardiac leiomodin2 binds to the sides of actin filaments and regulates the ATPase activity of myosin

Cardiac leiomodin2 binds to the sides of actin filaments and regulates the ATPase activity of myosin

Structural metamorphism and polymorphism in proteins on the brink of thermodynamic stability

Structural and dynamic characterization of the Golgi Reassembly and Stacking Protein (GRASP) in solution

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