Abstract
PKD2L1, also termed TRPP3 from the TRPP subfamily (polycystic TRP channels), is involved in the sour sensation and other pH-dependent processes. PKD2L1 is believed to be a nonselective cation channel that can be regulated by voltage, protons, and calcium. Despite its considerable importance, the molecular mechanisms underlying PKD2L1 regulations are largely unknown. Here, we determine the PKD2L1 atomic structure at 3.38 Å resolution by cryo-electron microscopy, whereby side chains of nearly all residues are assigned. Unlike its ortholog PKD2, the pore helix (PH) and transmembrane segment 6 (S6) of PKD2L1, which are involved in upper and lower-gate opening, adopt an open conformation. Structural comparisons of PKD2L1 with a PKD2-based homologous model indicate that the pore domain dilation is coupled to conformational changes of voltage-sensing domains (VSDs) via a series of π–π interactions, suggesting a potential PKD2L1 gating mechanism.
Highlights
PKD2: L521GD523 (PKD2L1), termed TRPP3 from the TRPP subfamily, is involved in the sour sensation and other pH-dependent processes
This PKD1L3/PKD2L1 complex is sensitive to Ca2+ impetuses, as well as mechanical stress and acid stimuli through off-responses, among which the acid sensing may be responsible for the function of sour taste and pH-dependent regulations[14,16,18,19,20]
To help understand the structures available far, we functionally validated our truncated channel (PKD2L1_64–629) with both Ca2+-induced response (ICE or influx-operated Ca2+ entry, ICa)[26] and acidevoked current response[16], resembling all the major characteristics established from wild-type (WT) PKD2L1
Summary
PKD2L1, termed TRPP3 from the TRPP subfamily (polycystic TRP channels), is involved in the sour sensation and other pH-dependent processes. Polycystin-2 like 1 protein (PKD2L1, termed TRPP3) and PKD2 ( termed TRPP2) comprise close relatives within the TRPP subfamily ( referred to as the polycystic TRP subfamily)[2], sharing high-sequence similarity (79% homology and 62% identity) They belong to group II TRP channels (TRPP and TRPML), which are characterized by large extracellular domains (exemplified by the polycystic domain and mucolipin domain, respectively) between the first two transmembrane (TM) segment sequences[3,4,5]. This structural feature is distinct from group I channels such as TRPV or classic voltage-gated ion channels (VGICs)[6]. Because of its considerable importance to PKD protein-related diseases, numerous in vitro and in vivo functional experiments have been performed to discover its mechanisms; the intricate regulatory mechanisms of PKD proteins remain to be uncovered
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