@unpublished{Swan:2022:10.1101/2022.10.13.511879,
author = {Swan, AH and Schindler, RFR and Savarese, M and Mayer, I and Rinné, S and Bleser, F and Schänzer, A and Hahn, A and Sabatelli, M and Perna, F and Chapman, K and Pfuhl, M and Spivey, AC and Decher, N and Udd, B and Tasca, G and Brand, T},
doi = {10.1101/2022.10.13.511879},
title = {Differential Effects of Mutations of Popeye Domain Containing Proteins on Heteromeric Interaction and Membrane Trafficking},
url = {http://dx.doi.org/10.1101/2022.10.13.511879},
year = {2022}
}

Download

TY  - UNPB
AB  - <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The Popeye domain containing (POPDC) genes encode sarcolemma-localised cAMP effector proteins. Mutations in<jats:italic>BVES (POPDC1)</jats:italic>and<jats:italic>POPDC2</jats:italic>have been associated with limb-girdle muscular dystrophy and cardiac arrhythmia. Muscle biopsies of affected patients display impaired membrane trafficking of both POPDC isoforms.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Biopsy material of patients carrying mutations in<jats:italic>BVES</jats:italic>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 interaction.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Patients carrying a novel homozygous variant,<jats:italic>BVES</jats:italic>(c.547G>T, p.V183F) displayed only a skeletal muscle pathology and a mild impairment of membrane trafficking of both POPDC isoforms. This is in contrast to variants such as<jats:italic>BVES</jats:italic>p.Q153X or<jats:italic>POPDC2</jats:italic>p.W188X, which 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.</jats:p></jats:sec><jats:sec><jats:title>Interpretat
AU  - Swan,AH
AU  - Schindler,RFR
AU  - Savarese,M
AU  - Mayer,I
AU  - Rinné,S
AU  - Bleser,F
AU  - Schänzer,A
AU  - Hahn,A
AU  - Sabatelli,M
AU  - Perna,F
AU  - Chapman,K
AU  - Pfuhl,M
AU  - Spivey,AC
AU  - Decher,N
AU  - Udd,B
AU  - Tasca,G
AU  - Brand,T
DO  - 10.1101/2022.10.13.511879
PY  - 2022///
TI  - Differential Effects of Mutations of Popeye Domain Containing Proteins on Heteromeric Interaction and Membrane Trafficking
UR  - http://dx.doi.org/10.1101/2022.10.13.511879
ER  - 

Download