Molecular evolution of the junctophilin gene family

Abstract

Junctophilins (JPHs) are members of a junctional membrane complex protein family important for the physical approximation of plasmalemmal and sarcoplasmic/endoplasmic reticulum membranes. As such, JPHs facilitate signal transduction in excitable cells between plasmalemmal voltagegated calcium channels and intracellular calcium release channels. To determine the molecular evolution of the JPH gene family, we performed a phylogenetic analysis of over 60 JPH genes from over 40 species and compared conservation across species and different isoforms. We found that JPHs are evolutionary highly conserved, in particular the membrane occupation and recognition nexus motifs found in all species. Our data suggest that an ancestral form of JPH arose at the latest in a common metazoan ancestor and that in vertebrates four isoforms arose, probably following two rounds of whole genome duplications. By combining multiple prediction techniques with sequence alignments, we also postulate the presence of new important functional regions and candidate sites for posttranslational modifications. The increasing number of available sequences yields significant insight into the molecular evolution of JPHs. Our analysis is consistent with the emerging concept that JPHs serve dual important functions in excitable cells: structural assembly of junctional membrane complexes and regulation of intracellular calcium signaling pathways.

A conserved membrane-binding domain targets proteins to organelle contact sites

“…S3). These findings suggest that, similar to Stim1, Stim2, junctionphilins and Ist2p (Deng et al, 2009;Ercan et al, 2009;Fischer et al, 2009;Garbino et al, 2009;Lewis, 2007;Wu et al, 2006), the TMD of Tcb2p is in the ER and its cytosolic domains binds the PM, causing it to be enriched at ER-PM contact sites.…”

( R )-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells

“…For example, SETD7 is recruited to the promoters of target genes by interacting with transcription factors such as NFκB (20). Secondly, SETD7 is the only methyltransferase that contains membrane occupation and recognition nexus (MORN) repeats that are found in proteins linking the membrane to the cytoskeleton (22). This observation suggests a potential cytoplasmic role for SETD7.…”

Junctophilin-4, a component of the endoplasmic reticulum–plasma membrane junctions, regulates Ca 2+ dynamics in T cells

“…Junctophilins contain eight repeats of the membrane occupation and recognition nexus (MORN) motifs that bind to phospholipids in the N terminus and a C-terminal ER membrane-spanning transmembrane segment (20,22). In this study, we observed expression of JP4 in both human and mouse T cells, which was further enhanced by TCR stimulation.…”