Sequence complexity of disordered protein

Abstract

Intrinsic disorder refers to segments or to whole proteins that fail to self-fold into fixed 3D structure, with such disorder sometimes existing in the native state. Here we report data on the relationships among intrinsic disorder, sequence complexity as measured by Shannon's entropy, and amino acid composition. Intrinsic disorder identified in protein crystal structures, and by nuclear magnetic resonance, circular dichroism, and prediction from amino acid sequence, all exhibit similar complexity distributions that are shifted to lower values compared to, but significantly overlapping with, the distribution for ordered proteins. Compared to sequences from ordered proteins, these variously characterized intrinsically disordered segments and proteins, and also a collection of lowcomplexity sequences, typically have obviously higher levels of protein-specific subsets of the following amino acids: R, K, E, P, and S, and lower levels of subsets of the following: C, W, Y, I, and V. The Swiss Protein database of sequences exhibits significantly higher amounts of both low-complexity and predicted-to-be-disordered segments as compared to a non-redundant set of sequences from the Protein Data Bank, providing additional data that nature is richer in disordered and low-complexity segments compared to the commonness of these features in the set of structurally characterized proteins.

CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices

“…Individual conformations can contain elements of secondary structure, but the population-weighted average conformation has only fractional secondary structure. These protein sequences have lower complexity than folded proteins and are enriched in arginine, lysine, glutamate, proline and serine, with fewer cysteine, tyrosine, tryptophan, isoleucine and valine residues 17 , as observed for the R region, with 30% charged residues. Prediction of intrinsically disordered proteins in complete genomes shows an increasing proportion of disordered proteins with increasing organism complexity: up to 14% of archaeal, 21% of bacterial and 41% of eukaryotic proteins are predicted to contain stretches of more than 50 disordered residues 18 .…”

Flavors of protein disorder

“…24 Briefly, reports on disordered regions identified by NMR, circular dichroism, or protease digestion were located by keyword searches of PubMed (http://www.ncbi.nlm.nih.gov/entrez). Additionally, starting from PDB_Select_25, 25 a nonredundant subset of the Protein Data Bank (PDB), 26 whose members have Ͻ25% sequence identity, we identified disordered regions in X-ray crystal structures by searching for residues whose backbone atoms are absent from the ATOMS list of their PDB files.…”

“…Because the amount of information about disordered proteins is rather limited, in accordance with previous work, 24 only first-order statistics of the 20 amino acids within a given window were used as attributes to prevent the "curse of dimensionality." 28 For example, attribute X A at a given position is calculated as the fraction of amino acid A (ALA or Alanine) within a window.…”

“…Very low complexity sequences are almost always disordered, whereas high complexity sequences can be ordered or disordered. 24,31 …”

CTCF terminal segments are unstructured

“…22,28 The circular dichroism spectra are similar to those observed for coil-like natively unfolded polypeptides; 28 changes in circular dichroism as a function of temperature also resemble the response of intrinsically disordered proteins. 27 Analysis of the CTCF sequence with disorder prediction algorithms 29,30 even identified regions in the terminal domains as likely to be unstructured (data not shown). We cannot rule out the possible existence of isolated helices or strands, but these elements are neither abundant nor assemble into an ordered fold.…”