An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs
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(2020) 21:88
BMC Molecular and Cell Biology
RESEARCH ARTICLE
Open Access
An interaction of heart disease-associated proteins POPDC1/2 with XIRP1 in transverse tubules and intercalated discs Ian Holt1,2*, Heidi R. Fuller1,2, Roland F. R. Schindler3, Sally L. Shirran4, Thomas Brand3 and Glenn E. Morris1,2
Abstract Background: Popeye domain-containing proteins 1 and 2 (POPDC1 and POPDC2) are transmembrane proteins involved in cyclic AMP-mediated signalling processes and are required for normal cardiac pacemaking and conduction. In order to identify novel protein interaction partners, POPDC1 and 2 proteins were attached to beads and compared by proteomic analysis with control beads in the pull-down of proteins from cultured human skeletal myotubes. Results: There were highly-significant interactions of both POPDC1 and POPDC2 with XIRP1 (Xin actin binding repeatcontaining protein 1), actin and, to a lesser degree, annexin A5. In adult human skeletal muscle, both XIRP1 and POPDC1/2 were present at the sarcolemma and in T-tubules. The interaction of POPDC1 with XIRP1 was confirmed in adult rat heart extracts. Using new monoclonal antibodies specific for POPDC1 and POPDC2, both proteins, together with XIRP1, were found mainly at intercalated discs but also at T-tubules in adult rat and human heart. Conclusions: Mutations in human POPDC1, POPDC2 and in human XIRP1, all cause pathological cardiac arrhythmias, suggesting a possible role for POPDC1/2 and XIRP1 interaction in normal cardiac conduction. Keywords: Popeye domain-containing, Xin actin binding repeat-containing, Cardiac conduction, Intercalated discs, Transverse tubules
Background Popeye domain containing protein 1 (POPDC1), also known as blood vessel epicardial substance (BVES), was first found in chicken heart by subtractive hybridisation [1, 2]. Popdc1 and two related gene family members, Popdc2 and Popdc3, were identified in mammals and shown to be developmentally regulated and preferentially expressed in cardiac and skeletal muscle [2]. Human POPDC1 is found on chromosome 6q21 along with POPDC3 in tandem array, whereas POPDC2 is found on human chromosome 3q13.33. The POPDC proteins are * Correspondence: [email protected] 1 Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK 2 School of Pharmacy and Bioengineering, Keele University, Keele ST5 5BG, UK Full list of author information is available at the end of the article
highly conserved throughout the animal kingdom, suggesting that they play an essential role [3]. POPDC proteins consist of a short extracellular Nterminal sequence which is glycosylated, three transmembrane domains, a conserved intracellular Popeye domain and a variable C-terminal domain which is isoform-specific, contains regions of low complexity and may be phosphorylated [4]. POPDC1 exists at the plasma membrane as a homodimer, which is stabilised by disulphide bonds [5, 6]. The predicted secondary structure of the Popeye domain contains a cyclic nucleotide binding domain, which binds the
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