Premium
The Structure and Function of COMMD1
Author(s) -
Rasmussen Zachary Andrew,
Fitzpatrick Kevin,
Choi Alice
Publication year - 2016
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.30.1_supplement.876.2
Subject(s) - in silico , c terminus , biochemistry , phosphatidylinositol , n terminus , plasma protein binding , microbiology and biotechnology , binding site , function (biology) , chemistry , amino acid , peptide sequence , biology , phosphorylation , gene
COMMD1 (Copper Metabolism Murr1 Domain 1) is a highly conserved, soluble 21 kD protein which functions in multiple pathways including copper transport. Despite having a variety of known functions, the mechanism of action of COMMD1 along with the structure is still unknown. The purpose of this research is to determine COMMD1's mechanism of action, specifically its ability to bind to phosphatidylinositol(4,5)‐ bis phosphate (PTDINS(4,5)P2), a well characterized substrate for cellular signaling proteins (3). COMMD1 is comprised of two domains, the N‐terminal VARiable Domain (VARD), and the C‐terminal (CTD), which contains the COMM domain. COMMD1 readily binds to phosphorylated phosphatidylinositols (PTDINS) with an increased specificity for PTDINS(4,5)P2. Additionally, COMMD1 forms high order oligomeric compounds spontaneously in vitro . The C‐terminus is required for PTDINS binding and performs PTDINS binding and oligomerization in the absence of the N‐terminus. An NMR structure for the non‐binding N‐terminus has been solved, and in silico prediction models of the CTD have been reported. The goals of this study are to identify critical amino acid residues for specific PTDINS(4,5)P2 binding, analyze relative binding affinities for different PTDINS(4,5)P2 lipids, and define structural characteristics of COMMD1 full‐length protein as well as N‐ and C‐terminal domains. The experimental approach uses biochemical and biophysical methods to study recombinant wild type and variant proteins. These studies are expected to inform continued in silico studies and in cell experiments to identify the biochemical mechanism of action that underlies COMMD1's pleiotropic functions.