LDB3

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LIM domain binding 3
Protein LDB3 PDB 1rgw.png
PDB rendering based on 1rgw.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LDB3 ; CMD1C; CMH24; CMPD3; CYPHER; LDB3Z1; LDB3Z4; LVNC3; MFM4; ORACLE; PDLIM6; ZASP
External IDs OMIM605906 MGI1344412 HomoloGene134626 GeneCards: LDB3 Gene
RNA expression pattern
PBB GE LDB3 213371 at tn.png
PBB GE LDB3 216887 s at tn.png
PBB GE LDB3 213717 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 11155 24131
Ensembl ENSG00000122367 ENSMUSG00000021798
UniProt O75112 Q9JKS4
RefSeq (mRNA) NM_001080114 NM_001039071
RefSeq (protein) NP_001073583 NP_001034160
Location (UCSC) Chr 10:
86.67 – 86.74 Mb
Chr 14:
34.53 – 34.59 Mb
PubMed search [1] [2]

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[edit]

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[edit]

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[edit]

Mutations in ZASP have been associated with myofibrillar myopathy,[13] dilated cardiomyopathy,[14][15][16] arrhythmogenic right ventricular cardiomyopathy,[17] noncompaction cardiomyopathy,[16][18] and muscular dystrophy.[13]

Interactions[edit]

The PDZ domain of ZASP binds the C-terminus of alpha actinin-2[19][20] and ZMs bind the rod domain of alpha actinin-2.[21] The LIM domains have been shown to interact with protein kinase C.[20][22] 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[edit]

References[edit]

  1. ^ a b "Entrez Gene: LDB3 LIM domain binding 3". 
  2. ^ Faulkner G, Pallavicini A, Formentin E, Comelli A, Ievolella C, Trevisan S, Bortoletto G, Scannapieco P, Salamon M, Mouly V, Valle G, Lanfranchi G (July 1999). "ZASP: a new Z-band alternatively spliced PDZ-motif protein". J. Cell Biol. 146 (2): 465–75. doi:10.1083/jcb.146.2.465. PMC 3206570. PMID 10427098. 
  3. ^ a b Sheikh F, Bang ML, Lange S, Chen J (Nov 2007). ""Z"eroing in on the role of Cypher in striated muscle function, signaling, and human disease". Trends in Cardiovascular Medicine 17 (8): 258–62. doi:10.1016/j.tcm.2007.09.002. PMID 18021935. 
  4. ^ "O75112-6". 
  5. ^ "O75112-5". 
  6. ^ "O75112-4". 
  7. ^ "O75112-3". 
  8. ^ "O75112-2". 
  9. ^ "O75112". 
  10. ^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  11. ^ a b Lin C, Guo X, Lange S, Liu J, Ouyang K, Yin X, Jiang L, Cai Y, Mu Y, Sheikh F, Ye S, Chen J, Ke Y, Cheng H (Oct 2013). "Cypher/ZASP is a novel A-kinase anchoring protein". The Journal of Biological Chemistry 288 (41): 29403–13. doi:10.1074/jbc.M113.470708. PMID 23996002. 
  12. ^ Bouaouina M, Jani K, Long JY, Czerniecki S, Morse EM, Ellis SJ, Tanentzapf G, Schöck F, Calderwood DA (Dec 2012). "Zasp regulates integrin activation". Journal of Cell Science 125 (Pt 23): 5647–57. doi:10.1242/jcs.103291. PMID 22992465. 
  13. ^ a b Selcen D, Engel AG (Feb 2005). "Mutations in ZASP define a novel form of muscular dystrophy in humans". Annals of Neurology 57 (2): 269–76. doi:10.1002/ana.20376. PMID 15668942. 
  14. ^ Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, Sinagra G, Lin JH, Vu TM, Zhou Q, Bowles KR, Di Lenarda A, Schimmenti L, Fox M, Chrisco MA, Murphy RT, McKenna W, Elliott P, Bowles NE, Chen J, Valle G, Towbin JA (Dec 2003). "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. doi:10.1016/j.jacc.2003.10.021. PMID 14662268. 
  15. ^ Arimura T, Hayashi T, Terada H, Lee SY, Zhou Q, Takahashi M, Ueda K, Nouchi T, Hohda S, Shibutani M, Hirose M, Chen J, Park JE, Yasunami M, Hayashi H, Kimura A (Feb 2004). "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. doi:10.1074/jbc.M311849200. PMID 14660611. 
  16. ^ a b Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, Sinagra G, Lin JH, Vu TM, Zhou Q, Bowles KR, Di Lenarda A, Schimmenti L, Fox M, Chrisco MA, Murphy RT, McKenna W, Elliott P, Bowles NE, Chen J, Valle G, Towbin JA (Dec 2003). "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. PMID 14662268. 
  17. ^ Lopez-Ayala JM, Ortiz-Genga M, Gomez-Milanes I, Lopez-Cuenca D, Ruiz-Espejo F, Sanchez-Munoz JJ, Oliva-Sandoval MJ, Monserrat L, Gimeno JR (Jul 2014). "A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy". Clinical Genetics. doi:10.1111/cge.12458. PMID 25041374. 
  18. ^ Xi Y, Ai T, De Lange E, Li Z, Wu G, Brunelli L, Kyle WB, Turker I, Cheng J, Ackerman MJ, Kimura A, Weiss JN, Qu Z, Kim JJ, Faulkner G, Vatta M (Oct 2012). "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. doi:10.1161/CIRCEP.111.969220. PMID 22929165. 
  19. ^ Faulkner G, Pallavicini A, Formentin E, Comelli A, Ievolella C, Trevisan S, Bortoletto G, Scannapieco P, Salamon M, Mouly V, Valle G, Lanfranchi G (Jul 1999). "ZASP: a new Z-band alternatively spliced PDZ-motif protein". The Journal of Cell Biology 146 (2): 465–75. PMID 10427098. 
  20. ^ a b Zhou Q, Ruiz-Lozano P, Martone ME, Chen J (Jul 1999). "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. PMID 10391924. 
  21. ^ Klaavuniemi T, Ylänne J (May 2006). "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. doi:10.1016/j.yexcr.2005.12.036. PMID 16476425. 
  22. ^ Kuroda S, Tokunaga C, Kiyohara Y, Higuchi O, Konishi H, Mizuno K, Gill GN, Kikkawa U (Dec 1996). "Protein-protein interaction of zinc finger LIM domains with protein kinase C". The Journal of Biological Chemistry 271 (49): 31029–32. PMID 8940095. 

Further reading[edit]

  • Marziliano N, Mannarino S, Nespoli L, Diegoli M, Pasotti M, Malattia C, Grasso M, Pilotto A, Porcu E, Raisaro A, Raineri C, Dore R, Maggio PP, Brega A, Arbustini E (May 2007). "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. doi:10.1002/ajmg.a.31653. PMID 17394203. 
  • Klaavuniemi T, Ylänne J (May 2006). "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. doi:10.1016/j.yexcr.2005.12.036. PMID 16476425. 
  • Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (Jan 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560. 
  • Arimura T, Hayashi T, Terada H, Lee SY, Zhou Q, Takahashi M, Ueda K, Nouchi T, Hohda S, Shibutani M, Hirose M, Chen J, Park JE, Yasunami M, Hayashi H, Kimura A (Feb 2004). "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. doi:10.1074/jbc.M311849200. PMID 14660611. 
  • Frey N, Olson EN (Apr 2002). "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. doi:10.1074/jbc.M200712200. PMID 11842093. 
  • Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. 
  • Passier R, Richardson JA, Olson EN (Apr 2000). "Oracle, a novel PDZ-LIM domain protein expressed in heart and skeletal muscle". Mechanisms of Development 92 (2): 277–84. doi:10.1016/S0925-4773(99)00330-5. PMID 10727866. 
  • Faulkner G, Pallavicini A, Formentin E, Comelli A, Ievolella C, Trevisan S, Bortoletto G, Scannapieco P, Salamon M, Mouly V, Valle G, Lanfranchi G (Jul 1999). "ZASP: a new Z-band alternatively spliced PDZ-motif protein". The Journal of Cell Biology 146 (2): 465–75. doi:10.1083/jcb.146.2.465. PMC 3206570. PMID 10427098. 
  • Zhou Q, Ruiz-Lozano P, Martone ME, Chen J (Jul 1999). "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. doi:10.1074/jbc.274.28.19807. PMID 10391924. 
  • Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (Jun 1998). "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. doi:10.1093/dnares/5.3.169. PMID 9734811. 
  • Lanfranchi G, Muraro T, Caldara F, Pacchioni B, Pallavicini A, Pandolfo D, Toppo S, Trevisan S, Scarso S, Valle G (Jan 1996). "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. doi:10.1101/gr.6.1.35. PMID 8681137. 

External links[edit]

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