LDB3

LDB3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4YDP
Identifiers
Aliases	LDB3 , CMD1C, CMPD3, CYPHER, LDB3Z1, LDB3Z4, LVNC3, MFM4, ORACLE, PDLIM6, ZASP, CMH24, LIM domain binding 3
External IDs	OMIM: 605906; MGI: 1344412; HomoloGene: 134626; GeneCards: LDB3; OMA:LDB3 - orthologs
Gene location (Human) Chr. Chromosome 10 (human) [1] Band 10q23.2 Start 86,666,785 bp [1] End 86,736,072 bp [1]
Gene location (Mouse) Chr. Chromosome 14 (mouse) [2] Band 14|14 B Start 34,248,560 bp [2] End 34,310,639 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Skeletal muscle tissue of biceps brachii muscle of thigh apex of heart body of tongue vastus lateralis muscle Skeletal muscle tissue of rectus abdominis left ventricle vena cava myocardium of left ventricle atrium Top expressed in triceps brachii muscle muscle of thigh medial head of gastrocnemius muscle temporal muscle sternocleidomastoid muscle ankle quadriceps femoris muscle tibialis anterior muscle digastric muscle vastus lateralis muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytoskeletal protein binding protein binding metal ion binding muscle alpha-actinin binding protein kinase C binding actin binding Cellular component cytoplasm perinuclear region of cytoplasm cell projection pseudopodium Z discdkac cytoskeleton stress fiber filamentous actin Biological process sarcomere organization heart development actin cytoskeleton organization muscle structure development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 11155 24131 Ensembl ENSG00000122367 ENSMUSG00000021798 UniProt O75112 Q9JKS4 RefSeq (mRNA) NM_001080114 NM_001080115 NM_001080116 NM_001171610 NM_001171611 NM_007078 NM_001368063 NM_001368064 NM_001368065 NM_001368066 NM_001368067 NM_001368068 NM_001039071 NM_001039072 NM_001039073 NM_001039074 NM_001039075 NM_001039076 NM_011918 RefSeq (protein) NP_001073583 NP_001073584 NP_001073585 NP_001165081 NP_001165082 NP_009009 NP_001354992 NP_001354993 NP_001354994 NP_001354995 NP_001354996 NP_001354997 NP_001034160 NP_001034161 NP_001034162 NP_001034163 NP_001034164 NP_001034165 NP_036048 Location (UCSC) Chr 10: 86.67 – 86.74 Mb Chr 14: 34.25 – 34.31 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. ^{[5] [6]} 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. ^[5]

Human ZASP can exist in cardiac and skeletal cells as six distinct isoforms, based on alternative splicing of 16 exons. ^[7] There are 2 ZASP short forms (Uniprot ID: O75112-6, 31.0 kDa, 283 amino acids; ^[8] and Uniprot ID: O75112-5, 35.6 kDa, 330 amino acids); ^[9] and 4 ZASP long forms (Uniprot ID: O75112-4, 42.8 kDa, 398 amino acids; ^[10] Uniprot ID: O75112-3, 50.6 kDa, 470 amino acids; ^[11] Uniprot ID: O75112-2, 66.6 kDa, 617 amino acids; ^[12] and Uniprot ID: O75112, 77.1 kDa, 727 amino acids). ^{[13] [14]} 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. ^[7]

Function

ZASP functions to maintain structural integrity of sarcomeres during contraction, and has been shown to be involved in protein kinase A signaling. ^[15] ZASP has also been shown to co-activate α5β1 integrins along with the protein TLN1. ^[16]

Clinical significance

Mutations in ZASP have been associated with myofibrillar myopathy, ^[17] dilated cardiomyopathy, ^{[18] [19]} arrhythmogenic right ventricular cardiomyopathy, ^[20] noncompaction cardiomyopathy, ^{[18] [21]} and muscular dystrophy. ^[17]

Interactions

The PDZ domain of ZASP binds the C-terminus of alpha actinin-2 ^{[6] [22]} and ZMs bind the rod domain of alpha actinin-2. ^[23] The LIM domains have been shown to interact with protein kinase C. ^{[22] [24]} The cardiac-specific region of ZASP encoded by exon 4 includes a ZP motif and binds a regulatory subunit of protein kinase A. ^[15]

See also

• Dilated cardiomyopathy
• Noncompaction cardiomyopathy

References

1. GRCh38: Ensembl release 89: ENSG00000122367 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021798 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: LDB3 LIM domain binding 3".
6. Faulkner G, Pallavicini A, Formentin E, Comelli A, Ievolella C, Trevisan S, et al. (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.
7. 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. PMC   2134983 . PMID   18021935.
8. "O75112-6". Archived from the original on 2015-06-13. Retrieved 2015-06-11.
9. "O75112-5". Archived from the original on 2015-06-13. Retrieved 2015-06-11.
10. "O75112-4". Archived from the original on 2015-06-13. Retrieved 2015-06-11.
11. "O75112-3". Archived from the original on 2015-06-13. Retrieved 2015-06-11.
12. "O75112-2". Archived from the original on 2015-06-13. Retrieved 2015-06-11.
13. "O75112". Archived from the original on 2015-06-13. Retrieved 2015-06-11.
14. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (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. PMC   4076475 . PMID   23965338.
15. Lin C, Guo X, Lange S, Liu J, Ouyang K, Yin X, et al. (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 . PMC   3795241 . PMID   23996002.
16. Bouaouina M, Jani K, Long JY, Czerniecki S, Morse EM, Ellis SJ, et al. (Dec 2012). "Zasp regulates integrin activation". Journal of Cell Science. 125 (Pt 23): 5647–57. doi:10.1242/jcs.103291. PMC   3575701 . PMID   22992465.
17. 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. S2CID   25733755.
18. Vatta M, Mohapatra B, Jimenez S, Sanchez X, Faulkner G, Perles Z, et al. (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.
19. 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.
20. Lopez-Ayala JM, Ortiz-Genga M, Gomez-Milanes I, Lopez-Cuenca D, Ruiz-Espejo F, Sanchez-Munoz JJ, et al. (Jul 2014). "A mutation in the Z-line Cypher/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy". Clinical Genetics. 88 (2): 172–6. doi:10.1111/cge.12458. hdl: 20.500.11940/2422 . PMID   25041374. S2CID   21822009.
21. Xi Y, Ai T, De Lange E, Li Z, Wu G, Brunelli L, et al. (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. PMC   4331025 . PMID   22929165.
22. 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.
23. 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.
24. Kuroda S, Tokunaga C, Kiyohara Y, Higuchi O, Konishi H, Mizuno K, et al. (Dec 1996). "Protein-protein interaction of zinc finger LIM domains with protein kinase C". The Journal of Biological Chemistry. 271 (49): 31029–32. doi: 10.1074/jbc.271.49.31029 . PMID   8940095.

Further reading

• Marziliano N, Mannarino S, Nespoli L, Diegoli M, Pasotti M, Malattia C, et al. (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. hdl: 2434/45968 . PMID   17394203. S2CID   20328643.
• 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, et al. (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.
• 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. S2CID   18254892.
• 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, et al. (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

• 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.