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Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking

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Alexander H. Swan, Roland F.R. Schindler, Marco Savarese, Isabelle Mayer, Susanne Rinné, Felix Bleser, Anne Schänzer, Andreas Hahn, Mario Sabatelli, Francesco Perna, Kathryn Chapman, Mark Pfuhl, Alan C. Spivey, Niels Decher, Bjarne Udd, Giorgio Tasca, Thomas Brand

Original languageEnglish
Article number4
JournalActa Neuropathologica Communications
Issue number1
PublishedDec 2023

Bibliographical note

Funding Information: Expert technical assistance of Mrs. Ursula Herbort-Brand is hereby gratefully acknowledged. We thank Stephen Rothery of the Facility for Imaging by Light Microscopy, Department of Medicine, Imperial College London who is in part funded by the British Heart Foundation (RE/18/4/34215) for his assistance and expertise in obtaining the sample images included in this work. Funding Information: This work was funded by the British Heart Foundation (PG/14/46/30911 and PG/19/13/34247) to TB and the Deutsche Forschungsgemeinschaft (DE1482/9-1) to ND. AHS was funded by an EPSRC/ British Heart Foundation co-funded Imperial Institute of Chemical Biology (ICB) Centre for Doctoral Training (CDT) PhD studentship (EP/S023518/1). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Publisher Copyright: © 2023, The Author(s).

King's Authors


The Popeye domain containing (POPDC) genes encode sarcolemma-localized cAMP effector proteins. Mutations in blood vessel epicardial substance (BVES) also known as POPDC1 and POPDC2 have been associated with limb-girdle muscular dystrophy and cardiac arrhythmia. Muscle biopsies of affected patients display impaired membrane trafficking of both POPDC isoforms. Biopsy material of patients carrying mutations in BVES were immunostained with POPDC antibodies. The interaction of POPDC proteins was investigated by co-precipitation, proximity ligation, bioluminescence resonance energy transfer and bimolecular fluorescence complementation. Site-directed mutagenesis was utilised to map the domains involved in protein–protein interaction. Patients carrying a novel homozygous variant, BVES (c.547G > T, p.V183F) displayed only a skeletal muscle pathology and a mild impairment of membrane trafficking of both POPDC isoforms. In contrast, variants such as BVES p.Q153X or POPDC2 p.W188X were associated with a greater impairment of membrane trafficking. Co-transfection analysis in HEK293 cells revealed that POPDC proteins interact with each other through a helix-helix interface located at the C-terminus of the Popeye domain. Site-directed mutagenesis of an array of ultra-conserved hydrophobic residues demonstrated that some of them are required for membrane trafficking of the POPDC1–POPDC2 complex. Mutations in POPDC proteins that cause an impairment in membrane localization affect POPDC complex formation while mutations which leave protein–protein interaction intact likely affect some other essential function of POPDC proteins.

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