Characterization of left‐handed beta helix‐domains, and identification and functional annotation of proteins containing such domains

Abstract

Only about 0.3% of the entries in UniProt database have manually curated annotation. Annotation at the molecular level often relies on low‐throughput one‐protein‐at‐a‐time approach. Computational methods bridge this gap by assigning function based on sequence and/or fold similarity. Left‐handed beta helix (LbH) consists of three repeating six‐stranded beta‐strands forming an 18‐mer turn of the helix. Analysis of LbH‐domains showed that variations are found in the number of residues in a beta‐strand (5‐7, 6 being the most common), number of turns (4–10) of the helix, insertions of one or more loops of variable length (0‐36 residues), and the location of loop insertion. An 18‐mer HMM profile was created which identifies LbH‐domain containing proteins using sequence as the only input; the number of false positives is zero when proteins tested were those with known 3D structures. 136 474 entries of TrEMBL database were found to contain LbH‐domain. Rules developed by analyzing LbH‐domain containing acyltransferases, gamma‐class carbonic anhydrases, and nucleotidyltransferases have led to the annotation of 17 389 TrEMBL entries which currently have no functional tag.

A closer look at Type I left-handed β-helices provides a better understanding in their sequence-structure relationship: towards their rational design

“…They were labelled according to their solvent exposition: buried (b), exposed (e) and partially exposed (p). 36 They are composed of six residues, hence termed hexad, four for the β-strand (B1, B2, B3, B4), and 2 for the turn (T1, T2). 29 Of note, in positions B1 and B3, the residues are oriented inwards, hence forming the hydrophobic core, whereas the others are oriented outwards of the helix (Figure 1d).…”

“…As such, they belong to the so-called "capping motifs" at the extremities of the helix that are the structural elements, belonging to the β-helix or not, responsible for the solubility of the protein. 7,[33][34][35][36] It has indeed been shown that removing capping motifs of β-solenoids, including left-handed β-helix, allows their self-assembly into fibers. 22,23,27 While these aspects were considered by Balaram and coworkers first, and later by Prabha and Balaji, they did not provide a specific analysis of the sequence of these N-terminal and C-terminal rungs.…”

“…22,23,27 While these aspects were considered by Balaram and coworkers first, and later by Prabha and Balaji, they did not provide a specific analysis of the sequence of these N-terminal and C-terminal rungs. 30,36 In this present work, we propose a sequence analysis of LβH-I by taking into account simultaneously that (i) LβH-I have three different faces due to the trimeric arrangement and that (ii) LβH-I is composed of three rungs of different nature. It has been performed only with sequences extracted from proteins of which the crystal structure in available in the Protein Data Bank (PDB), hence leaving no doubt on the position occupied in the LβH-I fold by each considered amino-acid.…”