Open AccessCa2+-Dependent Switch of Calmodulin Interaction Mode with Tandem IQ Motifs in the Scaffolding Protein IQGAP1
Author(s) -
Mingzhen Zhang,
Zhigang Li,
Hyunbum Jang,
Andrew C. Hedman,
David B. Sacks,
Ruth Nussinov
Publication year - 2019
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.9b00854
Subject(s) - iqgap1 , calmodulin , scaffold protein , chemistry , microbiology and biotechnology , biophysics , signal transduction , biology , biochemistry , enzyme
IQ domain GTPase-activating scaffolding protein 1 (IQGAP1) mediates cytoskeleton, cell migration, proliferation, and apoptosis events. Calmodulin (CaM) modulates IQGAP1 functions by binding to its four tandem IQ motifs. Exactly how CaM binds the IQ motifs and which functions of IQGAP1 CaM regulates and how are fundamental mechanistic questions. We combine experimental pull-down assays, mutational data, and molecular dynamics simulations to understand the IQ-CaM complexes with and without Ca 2+ at the atomic level. Apo-CaM favors the IQ3 and IQ4 motifs but not the IQ1 and IQ2 motifs that lack two hydrophobic residues for interactions with apo-CaM's hydrophobic pocket. Ca 2+ -CaM binds all four IQ motifs, with both N- and C-lobes tightly wrapped around each motif. Ca 2+ promotes IQ-CaM interactions and increases the amount of IQGAP1-loaded CaM for IQGAP1-mediated signaling. Collectively, we describe IQ-CaM binding in atomistic detail and feature the emergence of Ca 2+ as a key modulator of the CaM-IQGAP1 interactions.