LDB3

Last updated
LDB3
Protein LDB3 PDB 1rgw.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez

11155

24131

Ensembl

ENSG00000122367

ENSMUSG00000021798

UniProt

O75112

Q9JKS4

RefSeq (mRNA)
RefSeq (protein)
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

Related Research Articles

<span class="mw-page-title-main">Titin</span> Largest-known protein in human muscles

Titin is a protein that in humans is encoded by the TTN gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 244 individually folded protein domains connected by unstructured peptide sequences. These domains unfold when the protein is stretched and refold when the tension is removed.

<span class="mw-page-title-main">Plakoglobin</span> Mammalian protein found in Homo sapiens

Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia.

<span class="mw-page-title-main">Paxillin</span>

Paxillin is a protein that in humans is encoded by the PXN gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutations in PXN as well as abnormal expression of paxillin protein has been implicated in the progression of various cancers.

<span class="mw-page-title-main">Nebulette</span> Protein-coding gene in the species Homo sapiens

Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the NEBL gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardiac muscle and appears to regulate the length of actin thin filaments.

<span class="mw-page-title-main">TNNT2</span>

Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.

<span class="mw-page-title-main">Alpha-actinin-1</span> Protein-coding gene in the species Homo sapiens

Alpha-actinin-1 is a protein that in humans is encoded by the ACTN1 gene.

<span class="mw-page-title-main">ACTC1</span> Protein-coding gene in the species Homo sapiens

ACTC1 encodes cardiac muscle alpha actin. This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart.

<span class="mw-page-title-main">Alpha-actinin-2</span> Protein-coding gene in the species Homo sapiens

Alpha-actinin-2 is a protein which in humans is encoded by the ACTN2 gene. This gene encodes an alpha-actinin isoform that is expressed in both skeletal and cardiac muscles and functions to anchor myofibrillar actin thin filaments and titin to Z-discs.

<span class="mw-page-title-main">Alpha-actinin-4</span> Protein-coding gene in the species Homo sapiens

Alpha-actinin-4 is a protein that in humans is encoded by the ACTN4 gene.

<span class="mw-page-title-main">FLNC (gene)</span>

Filamin-C (FLN-C) also known as actin-binding-like protein (ABPL) or filamin-2 (FLN2) is a protein that in humans is encoded by the FLNC gene. Filamin-C is mainly expressed in cardiac and skeletal muscles, and functions at Z-discs and in subsarcolemmal regions.

<span class="mw-page-title-main">PDLIM5</span>

PDZ and LIM domain protein 5 is a protein that in humans is encoded by the PDLIM5 gene.

<span class="mw-page-title-main">MYOT</span> Mammalian protein found in Homo sapiens

Myotilin is a protein that in humans is encoded by the MYOT gene. Myotilin also known as TTID is a muscle protein that is found within the Z-disc of sarcomeres.

<span class="mw-page-title-main">MYL3</span> Protein-coding gene in the species Homo sapiens

Myosin essential light chain (ELC), ventricular/cardiac isoform is a protein that in humans is encoded by the MYL3 gene. This cardiac ventricular/slow skeletal ELC isoform is distinct from that expressed in fast skeletal muscle (MYL1) and cardiac atrial muscle (MYL4). Ventricular ELC is part of the myosin molecule and is important in modulating cardiac muscle contraction.

<span class="mw-page-title-main">NRAP</span> Protein-coding gene in the species Homo sapiens

Nebulin-related-anchoring protein(N-RAP) is a protein that in humans is encoded by the NRAP gene. N-RAP is a muscle-specific isoform belonging to the nebulin family of proteins. This family is composed of 5 members: N-RAP, nebulin, nebulette, LASP-1 and LASP-2. N-RAP is involved in both myofibrillar myogenesis during development and cell-cell connections in mature muscle.

<span class="mw-page-title-main">CSRP3</span>

Cysteine and glycine-rich protein 3 also known as cardiac LIM protein (CLP) or muscle LIM protein (MLP) is a protein that in humans is encoded by the CSRP3 gene.

<span class="mw-page-title-main">MYOZ2</span>

Myozenin-2, also referred to as Calsarcin-1, is a protein that in humans is encoded by the MYOZ2 gene. The Calsarcin-1 isoform is a muscle protein expressed in cardiac muscle and slow-twitch skeletal muscle, which functions to tether calcineurin to alpha-actinin at Z-discs, and inhibit the pathological cardiac hypertrophic response. This differs from the fast-skeletal muscle isoform, calsarcin-2.

<span class="mw-page-title-main">Myopalladin</span> Protein-coding gene in the species Homo sapiens

Myopalladin is a protein that in humans is encoded by the MYPN gene. Myopalladin is a muscle protein responsible for tethering proteins at the Z-disc and for communicating between the sarcomere and the nucleus in cardiac and skeletal muscle

<span class="mw-page-title-main">MYOZ1</span> Protein-coding gene in the species Homo sapiens

Myozenin-1 is a protein that in humans is encoded by the MYOZ1 gene.

<span class="mw-page-title-main">PDLIM3</span>

Actin-associated LIM protein (ALP), also known as PDZ and LIM domain protein 3 is a protein that in humans is encoded by the PDLIM3 gene. ALP is highly expressed in cardiac and skeletal muscle, where it localizes to Z-discs and intercalated discs. ALP functions to enhance the crosslinking of actin by alpha-actinin-2 and also appears to be essential for right ventricular chamber formation and contractile function.

Cytochrome c oxidase assembly factor 5 is a protein that in humans is encoded by the COA5 gene. This gene encodes an ortholog of yeast Pet191, which in yeast is a subunit of a large oligomeric complex associated with the mitochondrial inner membrane, and required for the assembly of the cytochrome c oxidase complex. Mutations in this gene are associated with mitochondrial complex IV deficiency.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000122367 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "Entrez Gene: LDB3 LIM domain binding 3".
  6. 1 2 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. 1 2 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".
  9. ↑ "O75112-5".
  10. ↑ "O75112-4".
  11. ↑ "O75112-3".
  12. ↑ "O75112-2".
  13. ↑ "O75112".
  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. 1 2 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. 1 2 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. 1 2 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. 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. 1 2 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

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

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.