Structure of the mammalian TRPM7, a magnesium channel required during embryonic development

Abstract

SignificanceIon channels are pore-forming proteins spanning biological membranes. Transient receptor potential ion channels are a subclass of ion channel proteins, characterized by nonselective permeability to cations such as sodium, calcium, magnesium, and zinc, and little voltage sensitivity; their gating is still an area of active investigation. TRPM6 and TRPM7 are ubiquitously expressed with prominent roles in early embryonic development. Uniquely, these channels also include an active kinase domain. The functions of TRPM6 and TRPM7 are correlated with proteolytic cleavage of the kinase domain, which is then translocated to the nucleus to phosphorylate histones and regulate gene expression. Here we describe the structure of the TRPM7 transmembrane regions and compare its features to other ion channels.

TRP ion channels: Proteins with conformational flexibility

“…The TRPM subfamily is composed of eight members with diverse features and functions [126]. The TRPM members for which cryo-EM structures have been solved in the closed or partially open conformations are TRPM2, TRPM4, TRPM7 and TRPM8 [127][128][129][130][131][132][133][134][135]. Their subunits are composed of six transmembranal segments, but at their N-terminal domains, they present four TRPM homology regions (MHR) and a C-terminal coiled-coil domain [127][128][129][130][131][132][133][134][135].…”

“…The protein kinase domain in TRPM7 induces phosphorylation of receptor tyrosine kinase (RTK)-signaling intermediates and chromatin modifications [150,151]. TRPM7 is permeable to Mg 2+ , Zn 2+ and Ca 2+ [152], and the cryo-EM structure of TRPM7 was obtained in the presence and absence of Mg 2+ [133].…”

“…Interestingly, the selectivity filter identified in TRPM7 (1045-FGE-1047), varies only on one residue to the selectivity filter described in TRPM4 (971-FGQ-973 in mouse TRPM4 channel), which is crucial to confer the monovalent selectivity of the latter. The lower gate was determined to be formed by I1093 and N1097 residues [133].…”

Structural mechanisms of transient receptor potential ion channels

“…Four Asp residues (DDDD), one from each subunit, form a negatively charged ring, offering an immediate impression that they are strategically positioned to either attract and/or directly coordinate cations; these Asp residues could also repel anions from the filter. Neutralization of this negative charge affects ion selectivity of many TRP channels, including TRPV1 (Chung et al, 2008), TRPV4 (Voets et al, 2002), TRPV5 (Nilius et al, 2001), TRPV6 (Voets et al, 2004b), TRPM7 (Duan et al, 2018b), fly TRP channels (Liu et al, 2007), TRPA1 (Christensen et al, 2016), and PKD2L1 (Fujimoto et al, 2011; DeCaen et al, 2016). TRPM4 and human TRPM2 (Guo et al, 2017; Winkler et al, 2017; Autzen et al, 2018; Duan et al, 2018c), but not Nematostella vectensis TRPM2 (Zhang et al, 2018b), are notable exceptions in having a glutamine at the outermost position of their selectivity filters (Fig.…”

“…3). In some cryo-EM maps of TRP channels, non-protein densities were indeed observed within the selectivity filter and thus interpreted to represent permeating cations (Chen et al, 2017; Guo et al, 2017; Hirschi et al, 2017; Wilkes et al, 2017; Duan et al, 2018b,c; Hughes et al, 2018a; Zhang et al, 2018b). In TRPV6 and TRPV4 crystal structures, the ion coordination sites were unambiguously confirmed by exploiting anomalous signals of more electron dense ions, such as Cs + , Gd 3+ , and Ba 2+ (Saotome et al, 2016; Deng et al, 2018).…”