@article{Swan:2023:10.1186/s40478-022-01501-w,
author = {Swan, A and Schindler, R 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 Kathryn, C and Pfuhl, M and Spivey, AC and Decher, N and Udd, B and Brand, T and Tasca, G},
doi = {10.1186/s40478-022-01501-w},
journal = {Acta Neuropathologica Communications},
pages = {1--25},
title = {Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking},
url = {http://dx.doi.org/10.1186/s40478-022-01501-w},
volume = {11},
year = {2023}
}

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TY  - JOUR
AB  - 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 membranetrafficking 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 askeletal 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 localisation affect POPDC complex formation while mutations which leave protein-protein interaction intact likely affect some other essential function of POPDC proteins.
AU  - Swan,A
AU  - Schindler,R
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  - Kathryn,C
AU  - Pfuhl,M
AU  - Spivey,AC
AU  - Decher,N
AU  - Udd,B
AU  - Brand,T
AU  - Tasca,G
DO  - 10.1186/s40478-022-01501-w
EP  - 25
PY  - 2023///
SN  - 2051-5960
SP  - 1
TI  - Differential effects of mutations of POPDC proteins on heteromeric interaction and membrane trafficking
T2  - Acta Neuropathologica Communications
UR  - http://dx.doi.org/10.1186/s40478-022-01501-w
UR  - https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-022-01501-w
UR  - http://hdl.handle.net/10044/1/101135
VL  - 11
ER  - 

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