Biology:LDB3

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


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
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.[1][2] 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.[1]

Human ZASP can exist in cardiac and skeletal cells as six distinct isoforms, based on alternative splicing of 16 exons.[3] There are 2 ZASP short forms (Uniprot ID: O75112-6, 31.0 kDa, 283 amino acids;[4] and Uniprot ID: O75112-5, 35.6 kDa, 330 amino acids);[5] and 4 ZASP long forms (Uniprot ID: O75112-4, 42.8 kDa, 398 amino acids;[6] Uniprot ID: O75112-3, 50.6 kDa, 470 amino acids;[7] Uniprot ID: O75112-2, 66.6 kDa, 617 amino acids;[8] and Uniprot ID: O75112, 77.1 kDa, 727 amino acids).[9][10] 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.[3]

Function

ZASP functions to maintain structural integrity of sarcomeres during contraction, and has been shown to be involved in protein kinase A signaling.[11] ZASP has also been shown to co-activate α5β1 integrins along with the protein TLN1.[12]

Clinical significance

Mutations in ZASP have been associated with myofibrillar myopathy,[13] dilated cardiomyopathy,[14][15] arrhythmogenic right ventricular cardiomyopathy,[16] noncompaction cardiomyopathy,[14][17] and muscular dystrophy.[13]

Interactions

The PDZ domain of ZASP binds the C-terminus of alpha actinin-2[2][18] and ZMs bind the rod domain of alpha actinin-2.[19] The LIM domains have been shown to interact with protein kinase C.[18][20] The cardiac-specific region of ZASP encoded by exon 4 includes a ZP motif and binds a regulatory subunit of protein kinase A.[11]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: LDB3 LIM domain binding 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11155. 
  2. ↑ 2.0 2.1 "ZASP: a new Z-band alternatively spliced PDZ-motif protein". J Cell Biol 146 (2): 465–75. July 1999. doi:10.1083/jcb.146.2.465. PMID 10427098. 
  3. ↑ 3.0 3.1 ""Z"eroing in on the role of Cypher in striated muscle function, signaling, and human disease". Trends in Cardiovascular Medicine 17 (8): 258–62. Nov 2007. doi:10.1016/j.tcm.2007.09.002. PMID 18021935. 
  4. ↑ "O75112-6". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O75112-6. 
  5. ↑ "O75112-5". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O75112-5. 
  6. ↑ "O75112-4". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O75112-4. 
  7. ↑ "O75112-3". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O75112-3. 
  8. ↑ "O75112-2". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O75112-2. 
  9. ↑ "O75112". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=O75112. 
  10. ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. Oct 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  11. ↑ 11.0 11.1 "Cypher/ZASP is a novel A-kinase anchoring protein". The Journal of Biological Chemistry 288 (41): 29403–13. Oct 2013. doi:10.1074/jbc.M113.470708. PMID 23996002. 
  12. ↑ "Zasp regulates integrin activation". Journal of Cell Science 125 (Pt 23): 5647–57. Dec 2012. doi:10.1242/jcs.103291. PMID 22992465. 
  13. ↑ 13.0 13.1 "Mutations in ZASP define a novel form of muscular dystrophy in humans". Annals of Neurology 57 (2): 269–76. Feb 2005. doi:10.1002/ana.20376. PMID 15668942. 
  14. ↑ 14.0 14.1 "Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction". Journal of the American College of Cardiology 42 (11): 2014–27. Dec 2003. doi:10.1016/j.jacc.2003.10.021. PMID 14662268. 
  15. ↑ "A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C". The Journal of Biological Chemistry 279 (8): 6746–52. Feb 2004. doi:10.1074/jbc.M311849200. PMID 14660611. 
  16. ↑ "A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy". Clinical Genetics 88 (2): 172–6. Jul 2014. doi:10.1111/cge.12458. PMID 25041374. 
  17. ↑ "Loss of function of hNav1.5 by a ZASP1 mutation associated with intraventricular conduction disturbances in left ventricular noncompaction". Circulation: Arrhythmia and Electrophysiology 5 (5): 1017–26. Oct 2012. doi:10.1161/CIRCEP.111.969220. PMID 22929165. 
  18. ↑ 18.0 18.1 "Cypher, a striated muscle-restricted PDZ and LIM domain-containing protein, binds to alpha-actinin-2 and protein kinase C". The Journal of Biological Chemistry 274 (28): 19807–13. Jul 1999. doi:10.1074/jbc.274.28.19807. PMID 10391924. 
  19. ↑ "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. 
  20. ↑ "Protein-protein interaction of zinc finger LIM domains with protein kinase C". The Journal of Biological Chemistry 271 (49): 31029–32. Dec 1996. doi:10.1074/jbc.271.49.31029. PMID 8940095. 

Further reading

External links

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



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