Biology:LDB3

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

LIM domain binding 3 (LDB3), also known as Z-band alternatively spliced PDZ-motif (ZASP), is a protein which in humans is encoded by the LDB3 gene. ZASP belongs to the Enigma subfamily of proteins and stabilizes the sarcomere (the basic units of muscles) during contraction, through interactions with actin in cardiac and skeletal muscles. Mutations in the ZASP gene has been associated with several muscular diseases.

Structure

ZASP is a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. ZASP interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family.

Human ZASP can exist in cardiac and skeletal cells as six distinct isoforms, based on alternative splicing of 16 exons. There are 2 ZASP short forms (Uniprot ID: O75112-6, 31.0 kDa, 283 amino acids; and Uniprot ID: O75112-5, 35.6 kDa, 330 amino acids); and 4 ZASP long forms (Uniprot ID: O75112-4, 42.8 kDa, 398 amino acids; Uniprot ID: O75112-3, 50.6 kDa, 470 amino acids; Uniprot ID: O75112-2, 66.6 kDa, 617 amino acids; and Uniprot ID: O75112, 77.1 kDa, 727 amino acids). All ZASP isoforms have an N-terminal PDZ domain; internal, conserved sequences known as ZASP-like motifs (ZMs); and the four long isoforms have three C-terminal LIM domains.

Function

ZASP functions to maintain structural integrity of sarcomeres during contraction, and has been shown to be involved in protein kinase A signaling. ZASP has also been shown to co-activate α5β1 integrins along with the protein TLN1.

Clinical significance

Mutations in ZASP have been associated with myofibrillar myopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, noncompaction cardiomyopathy, and muscular dystrophy.

Interactions

The PDZ domain of ZASP binds the C-terminus of alpha actinin-2 and ZMs bind the rod domain of alpha actinin-2. The LIM domains have been shown to interact with protein kinase C. The cardiac-specific region of ZASP encoded by exon 4 includes a ZP motif and binds a regulatory subunit of protein kinase A.

See also

• Dilated cardiomyopathy
• Noncompaction cardiomyopathy

Further reading

• "Barth syndrome associated with compound hemizygosity and heterozygosity of the TAZ and LDB3 genes". American Journal of Medical Genetics Part A 143A (9): 907–15. May 2007. doi:10.1002/ajmg.a.31653. PMID 17394203. 
• "Zasp/Cypher internal ZM-motif containing fragments are sufficient to co-localize with alpha-actinin--analysis of patient mutations". Experimental Cell Research 312 (8): 1299–311. May 2006. doi:10.1016/j.yexcr.2005.12.036. PMID 16476425. 
• "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. Jan 2006. doi:10.1101/gr.4039406. PMID 16344560. 
• "Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins". The Journal of Biological Chemistry 277 (16): 13998–4004. Apr 2002. doi:10.1074/jbc.M200712200. PMID 11842093. 
• "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. Nov 2000. doi:10.1101/gr.143000. PMID 11076863. 
• "Oracle, a novel PDZ-LIM domain protein expressed in heart and skeletal muscle". Mechanisms of Development 92 (2): 277–84. Apr 2000. doi:10.1016/S0925-4773(99)00330-5. PMID 10727866. 
• "Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research 5 (3): 169–76. Jun 1998. doi:10.1093/dnares/5.3.169. PMID 9734811. 
• "Identification of 4370 expressed sequence tags from a 3'-end-specific cDNA library of human skeletal muscle by DNA sequencing and filter hybridization". Genome Research 6 (1): 35–42. Jan 1996. doi:10.1101/gr.6.1.35. PMID 8681137. 

External links

• GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy
• Overview of all the structural information available in the PDB for UniProt: O75112 (Human LIM domain-binding protein 3) at the PDBe-KB.
• Overview of all the structural information available in the PDB for UniProt: Q9JKS4 (Mouse LIM domain-binding protein 3) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.