Hiding in plain sight: three chemically distinctα-helix types

Abstract

Linus Pauling in 1950 published a three-dimensional model for a universal protein secondary structure motif which he initially called the alpha-spiral. Jack Dunitz, then a postdoc in Pauling's lab suggested to Pauling that the term helix is more accurate than spiral when describing the right-handed peptide and protein coiled structures. Pauling agreed, hence the rise of the alpha-helix, and, by extension, the 'double helix' structure of DNA. Although structural biologists and protein chemists are familiar with varying polar and apolar characters of amino acids in alpha-helices, to non-experts the three chemically distinct alphahelix types classified here may hide in plain sight.

Structural informatic study of determined and AlphaFold2 predicted molecular structures of 13 human solute carrier transporters and their water-soluble QTY variants

“…Type I: the water-soluble hydrophilic alpha-helix, commonly water-soluble enzymes in the cellular cytosols and extracellular circulating proteins including antibodies, protein and peptide hormones and more; Type II: the water-insoluble hydrophobic alpha-helix commonly in www.nature.com/scientificreports/ transmembrane proteins including hormone receptors, transporters, ion channels, G protein-coupled receptors, photosynthesis systems; and Type III: the amphiphilic alpha-helix, like a Janus that have a hydrophobic face on one side and a hydrophilic face on the other side. These three chemically distinct alpha-helical types have very similar structures, regardless their hydrophobicity and hydrophilicity [45][46][47][48][49] . This is the molecular foundation of the QTY code.…”

Structural bioinformatics studies of six human ABC transporters and their AlphaFold2-predicted water-soluble QTY variants

“…The QTY code is a simple code that systematically replaces four hydrophobic amino acids leucine (L), isoleucine (I), valine (V), and phenylalanine (F) with three neutral and polar amino acids glutamine (Q), threonine (T), and tyrosine (Y), respectively (T replaces both I and V), since the respective electron density maps between L vs Q, I & V vs T, and F vs Y show remarkable structural similarities (Zhang et al, 2018 ; Zhang and Egli, 2022 ). After applying the QTY code, the hydrophobic amino acids are replaced with hydrophilic ones, and the transmembrane domain loses its hydrophobic characteristic.…”

“…Recently, CryoEM has significantly transformed structural biology (Henderson et al, 2011 ; Vinothkumar and Henderson, 2016 ). With the new structural biology revolution, the molecular structures of several human ABC transporters have been experimentally determined including ABCB7 (Protein Data Bank [PDB]: ) (Yan et al, 2022 ), ABCC8 (PDB: ) (Zhao and Mackinnon, 2021 ), ABCD1 (PDB: ) (Wang et al, 2021 ), ABCD4 (PDB: ) (Xu et al, 2019 ), ABCG1(PDB: ) (Rezaei et al, 2022 ), and ABCG5 (PDB: ) (Berge et al, 2000 ; Lee et al, 2001 ; Fong and Patel, 2021 ; Sun et al, 2021 ). However, given that each ABC transporter typically has two transmembrane domains with 5–11 membrane spanning alpha helices, experimental structural determination requires detergent screening for structural stabilization before protein purification can be carried out.…”

Point mutations in Arf1 reveal cooperative effects of the N-terminal region and myristate for GTPase-activating protein catalytic activity

“…Another possible mechanism for controlling protein-protein interactions is orientation. For example, the N-terminal extensions of Arf1 and Arf6 are 16 and 12 amino acids in length; given that alpha helices exhibit a characteristic 3.6 residues per helical turn (42), the packing of the helices at the C-terminal end of the HVRs may be different, which could in principle constrain the three-dimensional space available for the G domain to sample within the cytosol.…”