Details

Autor(en) / Beteiligte

• Lin, Xiaoyan
• Ruiz, Janelle
• Bajraktari, Ilda
• Ohman, Rachel
• Banerjee, Soojay
• Gribble, Katherine
• Kaufman, Joshua D.
• Wingfield, Paul T.
• Griggs, Robert C.
• Fischbeck, Kenneth H.
• Mankodi, Ami

Titel

Z-disc-associated, Alternatively Spliced, PDZ Motif-containing Protein (ZASP) Mutations in the Actin-binding Domain Cause Disruption of Skeletal Muscle Actin Filaments in Myofibrillar Myopathy

Ist Teil von

• The Journal of biological chemistry, 2014-05, Vol.289 (19), p.13615-13626

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• The core of skeletal muscle Z-discs consists of actin filaments from adjacent sarcomeres that are cross-linked by α-actinin homodimers. Z-disc-associated, alternatively spliced, PDZ motif-containing protein (ZASP)/Cypher interacts with α-actinin, myotilin, and other Z-disc proteins via the PDZ domain. However, these interactions are not sufficient to maintain the Z-disc structure. We show that ZASP directly interacts with skeletal actin filaments. The actin-binding domain is between the modular PDZ and LIM domains. This ZASP region is alternatively spliced so that each isoform has unique actin-binding domains. All ZASP isoforms contain the exon 6-encoded ZASP-like motif that is mutated in zaspopathy, a myofibrillar myopathy (MFM), whereas the exon 8–11 junction-encoded peptide is exclusive to the postnatal long ZASP isoform (ZASP-LΔex10). MFM is characterized by disruption of skeletal muscle Z-discs and accumulation of myofibrillar degradation products. Wild-type and mutant ZASP interact with α-actin, α-actinin, and myotilin. Expression of mutant, but not wild-type, ZASP leads to Z-disc disruption and F-actin accumulation in mouse skeletal muscle, as in MFM. Mutations in the actin-binding domain of ZASP-LΔex10, but not other isoforms, cause disruption of the actin cytoskeleton in muscle cells. These isoform-specific mutation effects highlight the essential role of the ZASP-LΔex10 isoform in F-actin organization. Our results show that MFM-associated ZASP mutations in the actin-binding domain have deleterious effects on the core structure of the Z-discs in skeletal muscle. The binding partners of the ZASP internal region that is mutated in zaspopathy are not yet known. The internal region of ZASP binds to skeletal muscle α-actin, and zaspopathy mutations cause actin disruption. ZASP mutations in the actin-binding domain are deleterious to the muscle Z-disc structure. ZASP-actin interaction expands the role of ZASP and defines the mechanism of zaspopathy.