ZASP Interacts with the Mechanosensing Protein Ankrd2 and p53 in the Signalling Network of Striated Muscle
2014
Authors
Martinelli, Valentina C.Kyle, W. Buck
Kojić, Snežana
Vitulo, Nicola
Li, Zhaohui
Belgrano, Anna
Maiuri, Paolo
Banks, Lawrence
Vatta, Matteo
Valle, Giorgio
Faulkner, Georgine
Article (Published version)
Metadata
Show full item recordAbstract
ZASP is a cytoskeletal PDZ-LIM protein predominantly expressed in striated muscle. It forms multiprotein complexes and plays a pivotal role in the structural integrity of sarcomeres. Mutations in the ZASP protein are associated with myofibrillar myopathy, left ventricular non-compaction and dilated cardiomyopathy. The ablation of its murine homologue Cypher results in neonatal lethality. ZASP has several alternatively spliced isoforms, in this paper we clarify the nomenclature of its human isoforms as well as their dynamics and expression pattern in striated muscle. Interaction is demonstrated between ZASP and two new binding partners both of which have roles in signalling, regulation of gene expression and muscle differentiation; the mechanosensing protein Ankrd2 and the tumour suppressor protein p53. These proteins and ZASP form a triple complex that appears to facilitate poly-SUMOylation of p53. We also show the importance of two of its functional domains, the ZM-motif and the PDZ d...omain. The PDZ domain can bind directly to both Ankrd2 and p53 indicating that there is no competition between it and p53 for the same binding site on Ankrd2. However there is competition for this binding site between p53 and a region of the ZASP protein lacking the PDZ domain, but containing the ZM-motif. ZASP is negative regulator of p53 in transactivation experiments with the p53-responsive promoters, MDM2 and BAX. Mutations in the ZASP ZM-motif induce modification in protein turnover. In fact, two mutants, A165V and A171T, were not able to bind Ankrd2 and bound only poorly to alpha-actinin2. This is important since the A165V mutation is responsible for zaspopathy, a well characterized autosomal dominant distal myopathy. Although the mechanism by which this mutant causes disease is still unknown, this is the first indication of how a ZASP disease associated mutant protein differs from that of the wild type ZASP protein.
Source:
PLoS One, 2014, 9, 3Publisher:
- Public Library Science, San Francisco
Funding / projects:
- Fondazione Cariparo, Italy
- Italian Ministry of Research [PRIN 20108XYHJS]
- Collaborative Research Programme, ICGEB, Italy [CRP/YUG-05-01]
- Complex diseases as a model system for phenotype modulation- structural and functional analysis of molecular biomarkers (RS-MESTD-Basic Research (BR or ON)-173008)
- NIH [R21-HL07887]
- Indiana University Health - Indiana University School of Medicine Strategic Research Initiative
DOI: 10.1371/journal.pone.0092259
ISSN: 1932-6203
PubMed: 24647531
WoS: 000333348500103
Scopus: 2-s2.0-84898670868
Institution/Community
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Martinelli, Valentina C. AU - Kyle, W. Buck AU - Kojić, Snežana AU - Vitulo, Nicola AU - Li, Zhaohui AU - Belgrano, Anna AU - Maiuri, Paolo AU - Banks, Lawrence AU - Vatta, Matteo AU - Valle, Giorgio AU - Faulkner, Georgine PY - 2014 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/780 AB - ZASP is a cytoskeletal PDZ-LIM protein predominantly expressed in striated muscle. It forms multiprotein complexes and plays a pivotal role in the structural integrity of sarcomeres. Mutations in the ZASP protein are associated with myofibrillar myopathy, left ventricular non-compaction and dilated cardiomyopathy. The ablation of its murine homologue Cypher results in neonatal lethality. ZASP has several alternatively spliced isoforms, in this paper we clarify the nomenclature of its human isoforms as well as their dynamics and expression pattern in striated muscle. Interaction is demonstrated between ZASP and two new binding partners both of which have roles in signalling, regulation of gene expression and muscle differentiation; the mechanosensing protein Ankrd2 and the tumour suppressor protein p53. These proteins and ZASP form a triple complex that appears to facilitate poly-SUMOylation of p53. We also show the importance of two of its functional domains, the ZM-motif and the PDZ domain. The PDZ domain can bind directly to both Ankrd2 and p53 indicating that there is no competition between it and p53 for the same binding site on Ankrd2. However there is competition for this binding site between p53 and a region of the ZASP protein lacking the PDZ domain, but containing the ZM-motif. ZASP is negative regulator of p53 in transactivation experiments with the p53-responsive promoters, MDM2 and BAX. Mutations in the ZASP ZM-motif induce modification in protein turnover. In fact, two mutants, A165V and A171T, were not able to bind Ankrd2 and bound only poorly to alpha-actinin2. This is important since the A165V mutation is responsible for zaspopathy, a well characterized autosomal dominant distal myopathy. Although the mechanism by which this mutant causes disease is still unknown, this is the first indication of how a ZASP disease associated mutant protein differs from that of the wild type ZASP protein. PB - Public Library Science, San Francisco T2 - PLoS One T1 - ZASP Interacts with the Mechanosensing Protein Ankrd2 and p53 in the Signalling Network of Striated Muscle IS - 3 VL - 9 DO - 10.1371/journal.pone.0092259 ER -
@article{ author = "Martinelli, Valentina C. and Kyle, W. Buck and Kojić, Snežana and Vitulo, Nicola and Li, Zhaohui and Belgrano, Anna and Maiuri, Paolo and Banks, Lawrence and Vatta, Matteo and Valle, Giorgio and Faulkner, Georgine", year = "2014", abstract = "ZASP is a cytoskeletal PDZ-LIM protein predominantly expressed in striated muscle. It forms multiprotein complexes and plays a pivotal role in the structural integrity of sarcomeres. Mutations in the ZASP protein are associated with myofibrillar myopathy, left ventricular non-compaction and dilated cardiomyopathy. The ablation of its murine homologue Cypher results in neonatal lethality. ZASP has several alternatively spliced isoforms, in this paper we clarify the nomenclature of its human isoforms as well as their dynamics and expression pattern in striated muscle. Interaction is demonstrated between ZASP and two new binding partners both of which have roles in signalling, regulation of gene expression and muscle differentiation; the mechanosensing protein Ankrd2 and the tumour suppressor protein p53. These proteins and ZASP form a triple complex that appears to facilitate poly-SUMOylation of p53. We also show the importance of two of its functional domains, the ZM-motif and the PDZ domain. The PDZ domain can bind directly to both Ankrd2 and p53 indicating that there is no competition between it and p53 for the same binding site on Ankrd2. However there is competition for this binding site between p53 and a region of the ZASP protein lacking the PDZ domain, but containing the ZM-motif. ZASP is negative regulator of p53 in transactivation experiments with the p53-responsive promoters, MDM2 and BAX. Mutations in the ZASP ZM-motif induce modification in protein turnover. In fact, two mutants, A165V and A171T, were not able to bind Ankrd2 and bound only poorly to alpha-actinin2. This is important since the A165V mutation is responsible for zaspopathy, a well characterized autosomal dominant distal myopathy. Although the mechanism by which this mutant causes disease is still unknown, this is the first indication of how a ZASP disease associated mutant protein differs from that of the wild type ZASP protein.", publisher = "Public Library Science, San Francisco", journal = "PLoS One", title = "ZASP Interacts with the Mechanosensing Protein Ankrd2 and p53 in the Signalling Network of Striated Muscle", number = "3", volume = "9", doi = "10.1371/journal.pone.0092259" }
Martinelli, V. C., Kyle, W. B., Kojić, S., Vitulo, N., Li, Z., Belgrano, A., Maiuri, P., Banks, L., Vatta, M., Valle, G.,& Faulkner, G.. (2014). ZASP Interacts with the Mechanosensing Protein Ankrd2 and p53 in the Signalling Network of Striated Muscle. in PLoS One Public Library Science, San Francisco., 9(3). https://doi.org/10.1371/journal.pone.0092259
Martinelli VC, Kyle WB, Kojić S, Vitulo N, Li Z, Belgrano A, Maiuri P, Banks L, Vatta M, Valle G, Faulkner G. ZASP Interacts with the Mechanosensing Protein Ankrd2 and p53 in the Signalling Network of Striated Muscle. in PLoS One. 2014;9(3). doi:10.1371/journal.pone.0092259 .
Martinelli, Valentina C., Kyle, W. Buck, Kojić, Snežana, Vitulo, Nicola, Li, Zhaohui, Belgrano, Anna, Maiuri, Paolo, Banks, Lawrence, Vatta, Matteo, Valle, Giorgio, Faulkner, Georgine, "ZASP Interacts with the Mechanosensing Protein Ankrd2 and p53 in the Signalling Network of Striated Muscle" in PLoS One, 9, no. 3 (2014), https://doi.org/10.1371/journal.pone.0092259 . .