Atypical Structural Tendencies Among Low-Complexity Domains in the Protein Data Bank Proteome

Abstract

A variety of studies have suggested that low-complexity domains (LCDs) tend to be intrinsically disordered and are relatively rare within structured proteins in the protein data bank (PDB). Although LCDs are often treated as a single class, we previously found that LCDs enriched in different amino acids can exhibit substantial differences in protein metabolism and function. Therefore, we wondered whether the structural conformations of LCDs are likewise dependent on which specific amino acids are enriched within each LCD. Here, we directly examined relationships between enrichment of individual amino acids and secondary structure preferences across the entire PDB proteome. Secondary structure preferences varied as a function of the identity of the amino acid enriched and its degree of enrichment. Furthermore, divergence in secondary structure profiles often occurred for LCDs enriched in physicochemically similar amino acids (e.g. valine vs. leucine), indicating that LCDs composed of related amino acids can have distinct secondary structure preferences. Comparison of LCD secondary structure preferences with numerous pre-existing secondary structure propensity scales resulted in relatively poor correlations for certain types of LCDs, indicating that these scales may not capture secondary structure preferences as sequence complexity decreases.Collectively, these observations provide a highly resolved view of structural preferences among LCDs parsed by the nature and magnitude of single amino acid enrichment.

A proposed role for the SARS‐CoV‐2 nucleocapsid protein in the formation and regulation of biomolecular condensates

“…B, Composition scan depicting the local S, R, and K content of the N protein sequence from SARS‐CoV‐2. The SARS‐CoV‐2 N protein sequence was scanned with a 20aa window and the percent composition of each amino acid was calculated at each position, similar to previous studies 90,91 . A region was considered an LCD if any single amino acid constituted ≥40% of the window sequence…”

“…The SARS-CoV-2 N protein sequence was scanned with a 20aa window and the percent composition of each amino acid was calculated at each position, similar to previous studies. 90,91 A region was considered an LCD if any single amino acid constituted ≥40% of the window sequence secondary (albeit lower) score corresponding to the RNAbinding NTD (Figure 2B,C). Additionally, the SR-domain passes the previously defined confidence threshold for the PSP method (Figure 2B), suggesting that the phase separation score is sufficiently high to be considered a likely LLPS protein.…”

Deciphering how naturally occurring sequence features impact the phase behaviors of disordered prion-like domains

“…Many of the protein components of stress granules are RNA-binding proteins (RBPs) that feature tandem RNA-binding domains and intrinsically disordered prion-like low complexity domains (PLCDs) 8, 9 . Mutations within PLCDs can cause neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) 10, 11 , and genetic translocation events that result in the expression of PLCD fusion proteins can cause multiple cancers 12, 13 .…”

Get closer and make hotspots: liquid–liquid phase separation in plants

“…A fascinating group of proteins involved in LLPS comprises the intrinsically disordered proteins (IDPs), which usually contain intrinsically disordered regions (IDRs), low-complexity sequence domains, or prion-like domains (PrDs) that exhibit a compositional bias for a small subset of polar and charged amino acids (Cascarina et al, 2020). IDPs are disordered and lack a well-defined 3D structure either throughout their full length or within IDRs (Habchi et al, 2014).…”