Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling

Abstract

Regulation, recognition and cell signaling involve the coordinated actions of many players. To achieve this coordination, each participant must have a valid identification (ID) that is easily recognized by the others. For proteins, these IDs are often within intrinsically disordered (also ID) regions. The functions of a set of well-characterized ID regions from a diversity of proteins are presented herein to support this view. These examples include both more recently described signaling proteins, such as p53, alpha-synuclein, HMGA, the Rieske protein, estrogen receptor alpha, chaperones, GCN4, Arf, Hdm2, FlgM, measles virus nucleoprotein, RNase E, glycogen synthase kinase 3beta, p21(Waf1/Cip1/Sdi1), caldesmon, calmodulin, BRCA1 and several other intriguing proteins, as well as historical prototypes for signaling, regulation, control and molecular recognition, such as the lac repressor, the voltage gated potassium channel, RNA polymerase and the S15 peptide associating with the RNA polymerase S-protein. The frequent occurrence and the common use of ID regions in important protein functions raise the possibility that the relationship between amino acid sequence, disordered ensemble and function might be the dominant paradigm for the molecular recognition that serves as the basis for signaling and regulation by protein molecules.

Alternative splicing modulates Kv channel clustering through a molecular ball and chain mechanism

“…To examine whether the channel tail functions as an entropic clock 14,25 able to time complex formation, we compared the kinetics of association and dissociation of the different channel tails to PDZ 2 (Fig. 2).…”

“…As realized by Aldrich and co-workers in the 1990 (ref. 17) and later rephrased by Dunker and colleagues 14,15 using current terminology, two principal requirements must be met for such a binding mechanism to be valid. First, one must show that the underlying binding reaction is entropy controlled, as determined by chain length, and second, that chain length times protein complex formation.…”

“…First, one must show that the underlying binding reaction is entropy controlled, as determined by chain length, and second, that chain length times protein complex formation. Thus, a 'ball and chain' sequence functions as an entropic clock 14,25 . Addressing these requirements in the context of the Kv channel-PSD-95 interaction requires thermodynamics, kinetics and energetic information, none of which is yet available.…”

Ewings family oncoproteins: drunk, disorderly and in search of partners

“…Another major hurdle was presented by the fact that (consistent with the functional data) native EAD structure is largely unfolded and is not npg amenable to analysis by classical methods such as crystallography or NMR. Very briefly the answer was to exploit a computational method [predictor of natural disordered regions (PONDR)] for the study of intrinsically disordered proteins (IDPs) [5]. PONDR typically predicts overall order/disorder and propensity for target-induced localised order, referred to as molecular recognition fragments/features (MoRFs).…”

Functional Anthology of Intrinsic Disorder. 2. Cellular Components, Domains, Technical Terms, Developmental Processes, and Coding Sequence Diversities Correlated with Long Disordered Regions

“…1, 2, 5, [8][9][10][11][12][13][14][15][16][17][18] Intrinsically disordered regions play a number of crucial roles in regulation, signaling and controlling processes where interactions with multiple partners and high-specificity/lowaffinity binding are involved. Many posttranslational modifications (including acetylation, hydroxylation, ubiquitination, methylation, phosphorylation, etc.)…”