Unfoldomics of Human Genetic Diseases: Illustrative Examples of Ordered and Intrinsically Disordered Members of the Human Diseasome

Midic, Uros; Oldfield, Christopher J.; Dunker, A. Keith; Obradović, Zoran; Uversky, Vladimir N.

doi:10.2174/092986609789839377

Cited by 61 publications

(47 citation statements)

References 146 publications

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“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] They are highly abundant in nature, [18][19][20][21][22] have intriguing structural and functional properties, 23 and are commonly involved in the pathogenesis of various diseases. 7,[24][25][26][27][28][29] IDPs/IDPRs are promiscuous binders, being known to interact in various protein-protein, protein-nucleic acid, and protein-small molecule interactions. Many IDPs/IDPRs are able to undergo at least partial disorder-to-order transition caused by their interactions with binding partners.…”

Section: Introductionmentioning

confidence: 99%

The intrinsic disorder alphabet. III. Dual personality of serine

Uversky

2015

Intrinsically Disordered Proteins

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Proteins are natural polypeptides consisting of 20 major amino acid residues, content and order of which in a given amino acid sequence defines the ability of a related protein to fold into unique functional state or to stay intrinsically disordered. Amino acid sequences code for both foldable (ordered) proteins/domains and for intrinsically disordered proteins (IDPs) and IDP regions (IDPRs), but these sequence codes are dramatically different. This difference starts with a very general property of the corresponding amino acid sequences, namely, their compositions. IDPs/IDPRs are enriched in specific disorder-promoting residues, whereas amino acid sequences of ordered proteins/domains typically contain more order-promoting residues. Therefore, the relative abundances of various amino acids in ordered and disordered proteins can be used to scale amino acids according to their disorder promoting potentials. This review continues a series of publications on the roles of different amino acids in defining the phenomenon of protein intrinsic disorder and represents serine, which is the third most disorder-promoting residue. Similar to previous publications, this review represents some physico-chemical properties of serine and the roles of this residue in structures and functions of ordered proteins, describes major posttranslational modifications tailored to serine, and finally gives an overview of roles of serine in structure and functions of intrinsically disordered proteins.

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Section: Introductionmentioning

confidence: 99%

The intrinsic disorder alphabet. III. Dual personality of serine

Uversky

2015

Intrinsically Disordered Proteins

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“…Intrinsically disordered proteins (IDPs) are relatively more prevalent among signaling and cancer-related proteins (Iakoucheva et al, 2002). The connection between disorder and diseases such as cancer, neurodegenerative conditions, amyloidosis, cardiovascular disease, and diabetes has been extensively explored in recent reviews (Uversky et al, 2008; Uros et al, 2009). Diseases arising from structural changes in proteins, loosely grouped as “conformational diseases” are caused not only by protein misfolding, but also by failures in post-translational modifications that result in aberrant interactions with physiological partners (Uversky et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of unique domains of Src family kinases

2014

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Members of the Src family of kinases (SFKs) are non-receptor tyrosine kinases involved in numerous signal transduction pathways. The catalytic, SH3 and SH2 domains are attached to the membrane-anchoring SH4 domain through the intrinsically disordered “Unique” domains, which exhibit strong sequence divergence among SFK members. In the last decade, structural and biochemical studies have begun to uncover the crucial role of the Unique domain in the regulation of SFK activity. This mini-review discusses what is known about the phosphorylation events taking place on the SFK Unique domains, and their biological relevance. The modulation by phosphorylation of biologically relevant inter- and intra- molecular interactions of Src, as well as the existence of complex phosphorylation/dephosphorylation patterns observed for the Unique domain of Src, reinforces the important functional role of the Unique domain in the regulation mechanisms of the Src kinases and, in a wider context, of intrinsically disordered regions in cellular processes.

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“…Thus, in some cases, the conditionally folded states (which may be transient) are presumed to be among the functional states of ID proteins. Mutation, truncation, and translocation of ID regions have been implicated in a variety of diseases (5,8,9). However, the mechanisms by which these ID regions regulate protein functions are largely unknown.…”

mentioning

confidence: 99%

Thermodynamic Dissection of the Intrinsically Disordered N-terminal Domain of Human Glucocorticoid Receptor

Motlagh

Chakuroff

et al. 2012

Journal of Biological Chemistry

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Background: Glucocorticoid receptor (GR) translational isoforms with different lengths in the intrinsically disordered (ID) N-terminal domain (NTD) have different activities. Results: The folded conformations of the NTDs are thermodynamically globular-like proteins with stabilities that correlate with transcriptional activity. Conclusion: Stability of the ID NTD is a functional regulator of GR. Significance: Activity modulation through ID stability tuning is a new regulatory paradigm.

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Unfoldomics of Human Genetic Diseases: Illustrative Examples of Ordered and Intrinsically Disordered Members of the Human Diseasome

Cited by 61 publications

References 146 publications

The intrinsic disorder alphabet. III. Dual personality of serine

The intrinsic disorder alphabet. III. Dual personality of serine

Phosphorylation of unique domains of Src family kinases

Thermodynamic Dissection of the Intrinsically Disordered N-terminal Domain of Human Glucocorticoid Receptor

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