Premium
Quaternary Structure Dynamics in Allostery ‐Aapplication to Mammalian Phenylalanine Hydroxylase
Author(s) -
Jaffe Eileen
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.360.2
Subject(s) - allosteric regulation , chemistry , protein subunit , protein quaternary structure , protein structure , biochemistry , structural biology , stereochemistry , biophysics , enzyme , biology , gene
There are an increasing number of proteins for which architecturally distinct homo‐multimers are implicated in alternate functions (e.g. porphobilinogen synthase, Ebola VP40, PKM2, glutaminase C, HMG CoA reductase, mechanosensitive ion channels, glucosamine‐6‐P synthase, HIV integrase), though the mechanism for multimer interconversion is often not well understood. Detailed analysis of porphobilinogen synthase suggests generalizations that can be applied to deciphering allosteric mechanism for other homo‐multimeric proteins, particularly those whose characteristics are consistent with the morpheein model of protein allostery. These characteristics are: 1) the difference between high‐activity and low‐activity multimers depends on inter‐subunit interactions that modulate active site access; 2) the pathway for multimer dissociation can expose large surface areas; 3) the conformational change that dictates assembly to architecturally distinct multimers is a hinge motion between domains of each subunit; 4) many single amino acid substitutions throughout the protein can change the intrinsic equilibrium between alternate multimers, with implication for understanding disease; 5) the position of the quaternary structure equilibrium responds to environmental factors such as pH, temperature, ionic strength, and small molecule ligand binding to multimer‐specific sites; 6) there are phylogenetic variations in sampling components of the quaternary structure equilibrium. In the context of a full‐length X‐ray crystal structure of mammalian phenylalanine hydroxylase, these principles are applied to deciphering allosteric regulation within the family of aromatic amino acid hydroxylases.